PEX11A (Peroxisomal membrane protein 11A, also known as PEX11-alpha or PMP28) is an inducible integral peroxisomal membrane protein that functions as a membrane elongation factor promoting peroxisome proliferation. It is one of three mammalian PEX11 paralogs (PEX11A, PEX11B, PEX11G). Unlike the constitutively expressed PEX11B, PEX11A expression is induced by peroxisome proliferators (e.g., clofibrate, 4-phenylbutyrate) and high-fat diet. PEX11A homo- and heterodimerizes (with PEX11G) and interacts with the fission factor FIS1, linking membrane elongation to the DRP1-dependent scission machinery. PEX11A-null mice show normal baseline peroxisomes but fail to proliferate peroxisomes in response to 4-PBA, and develop metabolic phenotypes (fatty liver, dyslipidemia) under dietary stress. No human disease mutations have been described.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
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GO:0005778
peroxisomal membrane
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: PEX11A is an integral peroxisomal membrane protein with two transmembrane helices, confirmed by multiple independent experimental studies. IBA annotation is phylogenetically well-supported across the PEX11 family.
Reason: Peroxisomal membrane localization is the most fundamental and well-established aspect of PEX11A biology. The original cloning paper (PMID:9714566) showed it is an integral peroxisomal membrane protein. Multiple IDA annotations from PMID:9714566, PMID:9792670, and PMID:20826455 also confirm this. The IBA annotation is consistent with all evidence.
Supporting Evidence:
PMID:9714566
PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus.
PMID:9792670
We report here the identification and characterization of two novel human peroxisomal membrane proteins, PEX11alpha and PEX11beta.
file:human/PEX11A/PEX11A-deep-research-falcon.md
PEX11A is an integral peroxisomal membrane protein that functions as a membrane elongation factor promoting peroxisome proliferation
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GO:0016559
peroxisome fission
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: PEX11A promotes peroxisome elongation (formation of juxtaposed elongated peroxisomes, JEPs) which is a prerequisite step for peroxisome fission/division. IBA annotation is phylogenetically well-supported across the PEX11 family from yeast to humans.
Reason: Peroxisome fission is the core biological process for PEX11 family proteins. Koch et al. (2010, PMID:20826455) showed that PEX11 family members drive membrane elongation and coordinate with fission machinery (FIS1, DRP1) for peroxisome division. The IBA reflects a conserved function across eukaryotes.
Supporting Evidence:
PMID:20826455
Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation.
PMID:20826455
Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression.
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|
GO:0005778
peroxisomal membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Combined automated annotation for peroxisomal membrane localization. Broader than the IBA annotation but consistent with extensive experimental evidence.
Reason: This IEA annotation is redundant with the IBA and multiple IDA annotations for the same term, but is not incorrect. PEX11A is unequivocally a peroxisomal membrane protein.
Supporting Evidence:
PMID:9714566
PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus.
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GO:0007031
peroxisome organization
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation derived from UniProtKB keyword mapping (Peroxisome biogenesis keyword). Peroxisome organization is a parent term of peroxisome fission. PEX11A is involved in peroxisome organization via its membrane elongation/fission role.
Reason: This is a broader parent term of peroxisome fission (GO:0016559). Since PEX11A is clearly involved in peroxisome fission, it is also involved in peroxisome organization. The IEA is consistent with the more specific IDA and IBA annotations for peroxisome fission.
Supporting Evidence:
PMID:9792670
Overexpression of PEX11alpha also induced peroxisome proliferation but at a much lower frequency than PEX11beta in our experimental system.
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GO:0016559
peroxisome fission
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation from InterPro domain mapping (IPR008733, PEX11 domain). Consistent with the core function of PEX11 family proteins in peroxisome fission.
Reason: The PEX11 domain (IPR008733/PF05648) is specifically associated with peroxisome fission function. This IEA is consistent with the IBA and IDA annotations for the same term.
Supporting Evidence:
PMID:20826455
Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression.
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GO:0016557
peroxisome membrane biogenesis
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: IEA annotation from Ensembl Compara ortholog transfer (from rat Pex11a, O70597). PEX11A promotes peroxisomal membrane elongation and contributes to membrane growth during peroxisome division. However, peroxisome membrane biogenesis specifically refers to formation of peroxisome membranes, which is more the domain of PEX3/PEX16/PEX19.
Reason: PEX11A is a membrane elongation factor that promotes peroxisome division, not a peroxisome membrane biogenesis factor per se. Peroxisome membrane biogenesis (GO:0016557) implies de novo formation of peroxisomal membranes, which is more specifically the role of PEX3, PEX16, and PEX19. PEX11A acts on pre-existing peroxisomal membranes to promote elongation and division. While there is some overlap, this term is misleading for PEX11A. The more accurate term is peroxisome fission (GO:0016559), already annotated.
Supporting Evidence:
PMID:9922452
We propose that peroxisomes may form by either of two pathways: one that involves PEX11-mediated division of preexisting peroxisomes, and another that involves PEX16-mediated formation of peroxisomes in the absence of preexisting peroxisomes.
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GO:0005777
peroxisome
|
IDA
PMID:19114594 The peroxisomal membrane protein import receptor Pex3p is di... |
ACCEPT |
Summary: In Matsuzaki & Fujiki (2008), PEX11A (as HA-Pex11alpha) was used as a control in experiments studying Pex3p targeting. The paper confirmed PEX11A localizes to peroxisomes but PEX11A was not the main subject of study; it was used as a negative control for Pex16p-mediated Pex3p recruitment.
Reason: While PEX11A was not the focus of this paper, it was used as a peroxisomal membrane marker/control, and its localization to peroxisomes was confirmed by immunofluorescence. The peroxisome localization annotation is well-supported, though the more specific peroxisomal membrane (GO:0005778) term is preferable.
Supporting Evidence:
PMID:19114594
We confirmed the complementing activity of PEX14-EGFP, HA-PEX13, HA-PEX12, HA-PEX10, HA-PEX2, and PEX3-Myc, using respective PEX-defective mutants, and the peroxisome division activity of HA-PEX11alpha with wild-type CHO cells.
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GO:0005777
peroxisome
|
IDA
PMID:18782765 Targeting of hFis1 to peroxisomes is mediated by Pex19p. |
ACCEPT |
Summary: In Delille & Schrader (2008), Pex11p-alpha-YFP was used as a peroxisomal membrane marker in COS-7 cells to specifically label peroxisomes for subcellular fractionation experiments studying hFis1 targeting. The paper confirmed peroxisomal localization of Pex11p-alpha.
Reason: PEX11A-YFP was explicitly shown to localize to peroxisomes by immunofluorescence. This is a well-supported localization annotation, though the more specific peroxisomal membrane (GO:0005778) is preferable.
Supporting Evidence:
PMID:18782765
Pex11pα-YFP, which exposes its N and C termini toward the cytosol ( 53 ), localized specifically to peroxisomes ( Fig
PMID:18782765
In contrast to other peroxisomal membrane proteins (for example, Pex11pβ) ( 46 ), no morphological alterations of the peroxisomal compartment were induced by Pex11pα-YFP, which might have influenced the association of hFis1 ( Fig
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|
GO:0005515
protein binding
|
IPI
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
REMOVE |
Summary: PEX11A was shown to interact with FIS1 (UniProtKB:Q9Y3D6) and PEX11G (UniProtKB:Q96HA9) by co-immunoprecipitation in Koch et al. (2010). However, 'protein binding' (GO:0005515) is too vague to be informative. The GOA file shows two separate IPI entries for this term, one for FIS1 and one for PEX11G. The interactions are functionally relevant: PEX11A-FIS1 interaction links membrane elongation to fission machinery recruitment, and PEX11A-PEX11G heterodimerization is part of the oligomerization required for function.
Reason: Per curation guidelines, 'protein binding' (GO:0005515) is uninformative and should be avoided. The specific interactions with FIS1 and PEX11G are better captured by the homodimerization activity annotation (GO:0042803) and the protein-containing complex annotation (GO:0032991). The functional significance is already captured by the peroxisome fission annotation (GO:0016559).
Supporting Evidence:
PMID:20826455
We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1
|
|
GO:0005777
peroxisome
|
IDA
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
ACCEPT |
Summary: Koch et al. (2010) showed PEX11A localizes to peroxisomes by fluorescence microscopy. This is the most comprehensive study of PEX11 family function.
Reason: Peroxisome localization is core to PEX11A function and well-supported by this study. The more specific term peroxisomal membrane (GO:0005778) is also annotated separately.
Supporting Evidence:
PMID:20826455
Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation.
|
|
GO:0016559
peroxisome fission
|
IDA
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
ACCEPT |
Summary: Koch et al. (2010) demonstrated that PEX11 family members (including PEX11A) are membrane elongation factors that coordinate peroxisome proliferation. Overexpression leads to juxtaposed elongated peroxisomes (JEPs), which represent intermediates in peroxisome division. Excess FIS1 can resolve JEPs into normal round peroxisomes, demonstrating the elongation-to-fission pathway.
Reason: This is the key experimental paper establishing PEX11 proteins as membrane elongation factors coordinating peroxisome fission. The IDA evidence is strong and directly supports this core function annotation.
Supporting Evidence:
PMID:20826455
Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression.
PMID:20826455
We show that excess of hFis1 but not of DRP1 is sufficient to fragment JEPs into normal round-shaped organelles
|
|
GO:0032991
protein-containing complex
|
IDA
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
ACCEPT |
Summary: Koch et al. (2010) demonstrated that PEX11A forms homodimers and heterodimers with PEX11G, and interacts with FIS1. The protein-containing complex annotation reflects these oligomerization properties. However, GO:0032991 is extremely generic.
Reason: PEX11A demonstrably forms homo- and heterodimeric complexes (with PEX11G) and interacts with FIS1 as part of the fission machinery. While the term is generic, it accurately reflects the oligomeric nature of PEX11A. A more specific complex term would be preferable but none exists in GO for the PEX11 complex.
Supporting Evidence:
PMID:20826455
We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1
|
|
GO:0042803
protein homodimerization activity
|
IDA
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
ACCEPT |
Summary: Koch et al. (2010) demonstrated PEX11A homodimerization by co-immunoprecipitation and showed that the C-terminal transmembrane domain (region 220-239) is required for homodimerization. Homodimerization is important for PEX11A membrane-shaping function.
Reason: Homodimerization was directly demonstrated experimentally and is functionally important for PEX11A's membrane elongation activity. This is a well-supported molecular function annotation. UniProt also notes that region 220-239 is required for homodimerization.
Supporting Evidence:
PMID:20826455
We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1
|
|
GO:0044375
regulation of peroxisome size
|
IDA
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
ACCEPT |
Summary: Koch et al. (2010) showed that overexpression of PEX11 family members leads to elongated peroxisomes (JEPs), directly demonstrating regulation of peroxisome morphology and size. This annotation captures the membrane remodeling aspect of PEX11A function.
Reason: PEX11A overexpression leads to elongated peroxisomes, directly demonstrating its role in regulating peroxisome size/morphology. This complements the peroxisome fission annotation by capturing the upstream membrane remodeling step.
Supporting Evidence:
PMID:20826455
Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation.
|
|
GO:0005778
peroxisomal membrane
|
IDA
PMID:9792670 Expression of PEX11beta mediates peroxisome proliferation in... |
ACCEPT |
Summary: Schrader et al. (1998) identified PEX11alpha and PEX11beta as novel human peroxisomal membrane proteins. PEX11alpha was characterized as a peroxisomal membrane protein whose expression is induced by peroxisome proliferators.
Reason: This is one of the original papers characterizing PEX11A as a peroxisomal membrane protein. The peroxisomal membrane localization is directly demonstrated.
Supporting Evidence:
PMID:9792670
We report here the identification and characterization of two novel human peroxisomal membrane proteins, PEX11alpha and PEX11beta.
|
|
GO:0005778
peroxisomal membrane
|
TAS
Reactome:R-HSA-1989753 |
ACCEPT |
Summary: Reactome entry R-HSA-1989753 describes the expression of PEX11A as part of the PPARA activates gene expression pathway. The TAS annotation for peroxisomal membrane localization is consistent with all experimental evidence.
Reason: The Reactome annotation correctly places PEX11A at the peroxisomal membrane. While the Reactome entry itself is minimal (just transcription/translation of PEX11A gene), the localization is well-established by multiple other sources.
Supporting Evidence:
PMID:9714566
PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus.
|
|
GO:0005778
peroxisomal membrane
|
IDA
PMID:9714566 Clofibrate-inducible, 28-kDa peroxisomal integral membrane p... |
ACCEPT |
Summary: Abe et al. (1998) cloned human PEX11 cDNA and showed it encodes a 28 kDa peroxisomal integral membrane protein (PMP28) with two transmembrane segments. Topology studies showed both N- and C-terminal parts are exposed to the cytosol. The protein was shown to be the clofibrate-inducible PMP28 previously identified from rat liver.
Reason: This is the original cloning and characterization paper for human PEX11A. It provides direct experimental evidence for peroxisomal membrane localization including topology mapping, co-migration with PMP28, and immunoreactivity with anti-PMP28 antibodies.
Supporting Evidence:
PMID:9714566
PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus.
PMID:9714566
Pex11p exposes both N- and C-terminal parts to the cytosol.
|
|
GO:0007031
peroxisome organization
|
IMP
PMID:9792670 Expression of PEX11beta mediates peroxisome proliferation in... |
ACCEPT |
Summary: Schrader et al. (1998) showed that overexpression of PEX11alpha induced peroxisome proliferation through a multistep process involving peroxisome elongation and division. PEX11alpha mRNA was induced more than 10-fold by peroxisome proliferators clofibrate and DEHP, suggesting a role in regulated peroxisome organization.
Reason: The IMP evidence from overexpression studies directly shows PEX11A involvement in peroxisome organization. This is a parent term of peroxisome fission, and the annotation is well-supported by the observed peroxisome proliferation phenotype upon overexpression.
Supporting Evidence:
PMID:9792670
Overexpression of PEX11alpha also induced peroxisome proliferation but at a much lower frequency than PEX11beta in our experimental system.
PMID:9792670
PEX11alpha mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents, and were induced more than 10-fold in response to the peroxisome proliferators clofibrate and di(2-ethylhexyl) phthalate.
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GO:0007165
signal transduction
|
IMP
PMID:9792670 Expression of PEX11beta mediates peroxisome proliferation in... |
REMOVE |
Summary: This annotation to signal transduction (GO:0007165) is based on the observation that PEX11alpha is transcriptionally induced by peroxisome proliferators (clofibrate, DEHP) and that its mRNA levels are highest in tissues sensitive to these agents. However, PEX11A itself is not a signaling molecule -- it is a downstream effector of the PPARalpha signaling pathway. Being transcriptionally regulated by a signal does not make PEX11A "involved in" signal transduction.
Reason: PEX11A is a target gene of PPARalpha-mediated signaling, not a component of the signal transduction machinery itself. The fact that PEX11A expression is induced by peroxisome proliferators reflects its regulation by the PPARalpha pathway, but PEX11A does not transduce signals. This is an over-annotation arising from conflating transcriptional response to a signal with participation in signal transduction. Signal transduction (GO:0007165) should be reserved for molecules that directly participate in signaling cascades (receptors, kinases, transcription factors, etc.), not their downstream structural/enzymatic targets.
Supporting Evidence:
PMID:9792670
PEX11alpha mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents, and were induced more than 10-fold in response to the peroxisome proliferators clofibrate and di(2-ethylhexyl) phthalate.
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GO:0005777
peroxisome
|
IDA
PMID:9922452 Peroxisome synthesis in the absence of preexisting peroxisom... |
ACCEPT |
Summary: In South & Gould (1999), PEX11alpha-myc was expressed in PBD061 cells (PEX16-deficient) and control PBD094 cells as one of many PMPs tested for import. PEX11alpha-myc was used as a peroxisomal membrane protein marker. The paper is primarily about PEX16 and de novo peroxisome formation, not about PEX11A function.
Reason: While PEX11A was not the focus of this study, it was used as a known peroxisomal membrane protein and its localization to peroxisomes was confirmed. The annotation is correct.
Supporting Evidence:
PMID:9922452
Similar results were observed in cells transfected with expression vectors designed to express other human PMPs, including PEX3myc (Kammerer et al., 1998), PEX10myc (Warren et al., 1998), PEX11αmyc (Schrader et al., 1998), PEX11βmyc (Schrader et al., 1998), and PEX13myc (Gould et al., 1996) (data not shown)
|
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GO:0046982
protein heterodimerization activity
|
IDA
PMID:20826455 PEX11 family members are membrane elongation factors that co... |
NEW |
Summary: Koch et al. (2010) demonstrated that PEX11A forms heterodimers with PEX11G in addition to homodimers. This heterodimerization activity is functionally significant for coordinating peroxisome proliferation. The homodimerization activity is already annotated (GO:0042803) but the heterodimerization with PEX11G is not captured.
Reason: PEX11A-PEX11G heterodimerization was directly demonstrated by Koch et al. (2010) and is an important aspect of PEX11A molecular function not currently captured by existing annotations. UniProt also states PEX11A is a heterodimer with PEX11G.
Supporting Evidence:
PMID:20826455
We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Target: Human PEX11A (also referred to in the literature as PEX11α; gene symbol PEX11A; peroxisomal membrane protein 11A). Evidence from mammalian peroxisome-division literature consistently treats mammals as having three PEX11 paralogs (PEX11a/α, PEX11b/β, PEX11γ; older nomenclature may label PEX11γ as “PEX11c”). PEX11α/PEX11A is described as inducible and not essential for baseline formation of functional peroxisomes, in contrast to PEX11β/PEX11B, which is more constitutively required for peroxisome division/dynamics and is associated with severe phenotypes when deficient. (koch2012pex11proteinsattract pages 1-2)
Scope note: Direct human PEX11A-specific mechanistic experiments are less common than those for PEX11B and PEX11γ (“PEX11c”). Where appropriate, I explicitly label when a claim is supported by PEX11 family evidence (isoform-level inference) or by mouse Pex11a ortholog studies rather than human PEX11A itself. (koch2010pex11familymembers pages 1-2, koch2012pex11proteinsattract pages 2-3, koch2012pex11proteinsattract pages 3-5, li2002pex11αisrequired pages 2-4)
Peroxisomes are dynamic organelles that can multiply via membrane growth and division. A widely used framework is a multistep process: (i) membrane remodeling/expansion and formation of tubular extensions, (ii) constriction, and (iii) membrane scission/division, yielding daughter peroxisomes. In mammals, this process is tightly coupled to shared fission machinery that is also used by mitochondria. (kumar2024theperoxisomean pages 11-13, subramani2023convergentanddivergent pages 1-3)
PEX11 family proteins are peroxisomal membrane proteins that act as membrane elongation factors, driving peroxisomal membrane deformation/tubulation and coordinating division. Human PEX11 isoforms are described as small basic membrane proteins with predicted membrane-embedded regions, and experimental manipulations (overexpression) induce elongated/juxtaposed elongated peroxisomes (JEPs)—a hallmark phenotype used to assay membrane-shaping function. (koch2010pex11familymembers pages 1-2, koch2012pex11proteinsattract pages 1-2)
A core fission GTPase in mammals is DRP1 (DNM1L). Recruitment of DRP1 to peroxisomes involves tail-anchored adaptors MFF and FIS1 at the peroxisomal membrane, and DRP1 oligomerization at constriction sites drives scission. Peroxisomes and mitochondria share several of these components, consistent with coordinated organelle dynamics. (kumar2024theperoxisomean pages 11-13, subramani2023convergentanddivergent pages 1-3)
Localization: Mammalian PEX11 proteins (including PEX11a/PEX11A) localize to the peroxisomal membrane. (koch2012pex11proteinsattract pages 2-3, koch2012pex11proteinsattract pages 1-2)
Topology (best-supported at family level): Detailed topology mapping in Koch & Brocard (2012) is strongest for PEX11γ (“PEX11c”) and supports an integral membrane configuration with cytosolic exposure of termini and membrane-embedded hydrophobic regions. These structural features are presented as characteristic of mammalian PEX11 proteins and are commonly used as inference for PEX11A. (koch2012pex11proteinsattract pages 2-3, koch2012pex11proteinsattract pages 3-5)
PEX11A (PEX11α) is positioned as an inducible regulator of peroxisome proliferation rather than the constitutive “baseline” division driver.
PEX11 proteins help couple membrane elongation to scission by interacting with, and influencing recruitment of, fission machinery.
Koch & Brocard (2012) report interactions between PEX11 proteins and Mff and association with hFis1, consistent with a model in which PEX11 proteins help recruit/organize fission machinery at peroxisomes. (koch2012pex11proteinsattract pages 1-2, koch2012pex11proteinsattract pages 10-11)
Family-level mechanistic model from authoritative review:
PEX11A is described as environmentally inducible, consistent with a role in adaptive peroxisome proliferation. (koch2012pex11proteinsattract pages 1-2)
A classic, direct functional test of PEX11α (Pex11a) involvement in peroxisome proliferation comes from Li et al. (2002):
The evidence here supports a nuanced interpretation:
Li et al. (2002) report that PEX11α-null mice have normal baseline peroxisome abundance and no obvious external phenotype under the conditions examined, supporting the idea that PEX11A is not essential for maintaining baseline peroxisome number. (li2002pex11αisrequired pages 2-4)
Although these data are from mouse Pex11a (ortholog of human PEX11A), they provide the strongest organism-level evidence for PEX11A-linked pathways:
A 2022 expert review on peroxisome dynamics disorders notes that no human patients with PEX11A mutations had been described at the time of writing, and that PEX11α roles appear less clear than PEX11β in division disorders (with PEX11β-linked phenotypes better established). (carmichael2022fissionimpossible(?)—new pages 15-16)
Plessner et al. (2024) performed an expression meta-analysis spanning brain, heart, kidney, liver (humans and mice), integrating transcriptomics and proteomics:
Supporting figures from this study (useful for a visual overview of where PEX11 family sits in pathways and for expression heatmaps) were retrieved. (plessner2024tissuespecificrolesof media 02bf5939, plessner2024tissuespecificrolesof media af8b9ce7)
Subramani et al. (2023) synthesize convergent/divergent mechanisms of mitochondrial and peroxisomal division. For PEX11-family proteins (including HsPEX11α), notable updates include:
Plessner et al. (2024) represents a 2024 effort to unify tissue expression (RNA + protein) for peroxisomal pathways and provides a quantitative scaffold for where peroxisomal biogenesis/fission machinery is available vs where metabolic enzymes are enriched. (plessner2024tissuespecificrolesof pages 1-2, plessner2024tissuespecificrolesof pages 8-10)
Kumar et al. (2024) provide a current review of peroxisome biogenesis, import, and dynamics. Their peroxisome division section emphasizes PEX11β rather than PEX11A, but it is still important for interpreting PEX11A within mammalian division pathways (shared machinery and alternative division routes). (kumar2024theperoxisomean pages 11-13)
PEX11 proteins are used experimentally as tools to manipulate peroxisome morphology and abundance:
The finding that PEX11α is required for 4-PBA–induced proliferation but not for classical PPARα-driven proliferation supports using stimulus-specific proliferation assays to dissect signaling-to-organelle remodeling mechanisms and identify genes required for distinct proliferation programs. (li2002pex11αisrequired pages 2-4)
Mouse Pex11a phenotypes (fatty liver, dyslipidemia/obesity) position PEX11A as a candidate modulator of lipid homeostasis under metabolic stress, motivating studies that connect peroxisome dynamics (abundance/surface area and contacts) to systemic metabolic disease. (weng2013pex11αdeficiencyimpairs pages 4-5, chen2019pex11adeficiencycauses pages 1-2)
| Claim/Fact | Implications for PEX11A Function | Key Supporting Evidence | Primary Sources | Notes/Limitations |
|---|---|---|---|---|
| Peroxisomal Localization | Integral membrane protein functioning at the peroxisome surface. | PEX11 family members localize to peroxisomes; PEX11$\alpha$ contains transmembrane domains and exposes N/C-termini to cytosol. | Koch & Brocard (2012) (koch2012pex11proteinsattract pages 1-2, koch2012pex11proteinsattract pages 2-3); Li et al. (2002) (li2002pex11αisrequired pages 1-2) | Topology often inferred from PEX11 family homology (PEX11$\beta$/$\gamma$). |
| Membrane Elongation | Drivers of the initial step of peroxisome division (tubulation/elongation). | Overexpression of PEX11 proteins induces formation of juxtaposed elongated peroxisomes (JEPs) and membrane tubulation. | Koch et al. (2010) (koch2010pex11familymembers pages 1-2); Koch & Brocard (2012) (koch2012pex11proteinsattract pages 1-2) | PEX11$\alpha$ is less potent than PEX11$\beta$ in some assays; requires dimerization/oligomerization. |
| Fission Machinery Recruitment | Coordinates membrane deformation with scission by recruiting GTPases. | PEX11 proteins interact with fission factors like FIS1 and MFF to recruit DRP1 (dynamin-like protein) to constriction sites. | Koch & Brocard (2012) (koch2012pex11proteinsattract pages 1-2, koch2012pex11proteinsattract pages 10-11); Subramani et al. (2023) (subramani2023convergentanddivergent pages 1-3) | Direct PEX11A-specific interaction data is less abundant than for PEX11$\beta$. |
| Inducibility & Regulation | Serves as an inducible regulator of peroxisome abundance rather than a constitutive maintenance factor. | PEX11$\alpha$ expression is low in basal conditions but strongly induced by peroxisome proliferators (e.g., fibrates, 4-PBA) and high-fat diets. | Li et al. (2002) (li2002pex11αisrequired pages 1-2, li2002pex11αisrequired pages 10-11); Weng et al. (2013) (weng2013pex11αdeficiencyimpairs pages 8-8) | PEX11$\beta$ is the constitutive isoform; PEX11$\alpha$ levels respond to metabolic demand. |
| Non-Essential Baseline Role | Loss does not prevent peroxisome formation but impairs stress response/expansion. | Pex11a-null mice are viable with normal baseline peroxisome numbers but fail to proliferate peroxisomes upon stimulation (e.g., 4-PBA). | Li et al. (2002) (li2002pex11αisrequired pages 2-4); Carmichael et al. (2022) (carmichael2022fissionimpossible(?)—new pages 15-16) | Contrast with Pex11b-null mice which show severe, lethal Zellweger-like phenotypes. |
| Metabolic Phenotypes | Critical for lipid homeostasis and fatty acid oxidation under metabolic stress. | Pex11a deficiency leads to hepatic steatosis, dyslipidemia, obesity, and reduced fatty acid $\beta$-oxidation in mice fed high-fat diets. | Weng et al. (2013) (weng2013pex11αdeficiencyimpairs pages 4-5); Chen et al. (2019) (chen2019pex11adeficiencycauses pages 1-2) | Metabolic roles likely stem from regulating organelle abundance/surface area for flux. |
| Tissue Expression Context | Functionally linked to tissues with high metabolic/lipid processing load. | High expression corresponds to liver and kidney where peroxisomal $\beta$-oxidation and $\alpha$-oxidation are most active; induced by PPAR$\alpha$. | Plessner et al. (2024) (plessner2024tissuespecificrolesof pages 8-10, plessner2024tissuespecificrolesof media 02bf5939); Weng et al. (2013) (weng2013pex11αdeficiencyimpairs pages 8-8) | PEX11A expression is distinct from the more ubiquitous PEX11B. |
Table: Key functional characteristics of PEX11A derived from primary literature, highlighting its specific role as an inducible membrane elongation factor involved in lipid metabolism and stress response, distinct from the constitutive PEX11B.
References
(koch2012pex11proteinsattract pages 1-2): Johannes Koch and Cécile Brocard. Pex11 proteins attract mff and human fis1 to coordinate peroxisomal fission. Journal of Cell Science, 125:3813-3826, Aug 2012. URL: https://doi.org/10.1242/jcs.102178, doi:10.1242/jcs.102178. This article has 128 citations and is from a domain leading peer-reviewed journal.
(koch2010pex11familymembers pages 1-2): Johannes Koch, Kornelija Pranjic, Anja Huber, Adolf Ellinger, Andreas Hartig, Friedrich Kragler, and Cécile Brocard. Pex11 family members are membrane elongation factors that coordinate peroxisome proliferation and maintenance. Journal of Cell Science, 123:3389-3400, Oct 2010. URL: https://doi.org/10.1242/jcs.064907, doi:10.1242/jcs.064907. This article has 201 citations and is from a domain leading peer-reviewed journal.
(koch2012pex11proteinsattract pages 2-3): Johannes Koch and Cécile Brocard. Pex11 proteins attract mff and human fis1 to coordinate peroxisomal fission. Journal of Cell Science, 125:3813-3826, Aug 2012. URL: https://doi.org/10.1242/jcs.102178, doi:10.1242/jcs.102178. This article has 128 citations and is from a domain leading peer-reviewed journal.
(koch2012pex11proteinsattract pages 3-5): Johannes Koch and Cécile Brocard. Pex11 proteins attract mff and human fis1 to coordinate peroxisomal fission. Journal of Cell Science, 125:3813-3826, Aug 2012. URL: https://doi.org/10.1242/jcs.102178, doi:10.1242/jcs.102178. This article has 128 citations and is from a domain leading peer-reviewed journal.
(li2002pex11αisrequired pages 2-4): Xiaoling Li, Eveline Baumgart, Gao-Xiang Dong, James C. Morrell, Gerardo Jimenez-Sanchez, David Valle, Kirby D. Smith, and Stephen J. Gould. Pex11α is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Molecular and Cellular Biology, 22:8226-8240, Dec 2002. URL: https://doi.org/10.1128/mcb.22.23.8226-8240.2002, doi:10.1128/mcb.22.23.8226-8240.2002. This article has 197 citations and is from a domain leading peer-reviewed journal.
(kumar2024theperoxisomean pages 11-13): Rechal Kumar, Markus Islinger, Harley Worthy, Ruth Carmichael, and Michael Schrader. The peroxisome: an update on mysteries 3.0. Histochemistry and Cell Biology, 161:99-132, Jan 2024. URL: https://doi.org/10.1007/s00418-023-02259-5, doi:10.1007/s00418-023-02259-5. This article has 73 citations and is from a peer-reviewed journal.
(subramani2023convergentanddivergent pages 1-3): Suresh Subramani, Nandini Shukla, and Jean-Claude Farre. Convergent and divergent mechanisms of peroxisomal and mitochondrial division. The Journal of Cell Biology, Aug 2023. URL: https://doi.org/10.1083/jcb.202304076, doi:10.1083/jcb.202304076. This article has 7 citations.
(koch2012pex11proteinsattract pages 10-11): Johannes Koch and Cécile Brocard. Pex11 proteins attract mff and human fis1 to coordinate peroxisomal fission. Journal of Cell Science, 125:3813-3826, Aug 2012. URL: https://doi.org/10.1242/jcs.102178, doi:10.1242/jcs.102178. This article has 128 citations and is from a domain leading peer-reviewed journal.
(subramani2023convergentanddivergent pages 12-13): Suresh Subramani, Nandini Shukla, and Jean-Claude Farre. Convergent and divergent mechanisms of peroxisomal and mitochondrial division. The Journal of Cell Biology, Aug 2023. URL: https://doi.org/10.1083/jcb.202304076, doi:10.1083/jcb.202304076. This article has 7 citations.
(li2002pex11αisrequired pages 1-2): Xiaoling Li, Eveline Baumgart, Gao-Xiang Dong, James C. Morrell, Gerardo Jimenez-Sanchez, David Valle, Kirby D. Smith, and Stephen J. Gould. Pex11α is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Molecular and Cellular Biology, 22:8226-8240, Dec 2002. URL: https://doi.org/10.1128/mcb.22.23.8226-8240.2002, doi:10.1128/mcb.22.23.8226-8240.2002. This article has 197 citations and is from a domain leading peer-reviewed journal.
(weng2013pex11αdeficiencyimpairs pages 4-5): Huachun Weng, Xu Ji, Yukiko Naito, Kosuke Endo, Xiao Ma, Rie Takahashi, Chunshen Shen, Go Hirokawa, Yasue Fukushima, and Naoharu Iwai. Pex11α deficiency impairs peroxisome elongation and division and contributes to nonalcoholic fatty liver in mice. American journal of physiology. Endocrinology and metabolism, 304 2:E187-96, Jan 2013. URL: https://doi.org/10.1152/ajpendo.00425.2012, doi:10.1152/ajpendo.00425.2012. This article has 53 citations.
(chen2019pex11adeficiencycauses pages 1-2): Congcong Chen, Hongwei Wang, Bicheng Chen, Deyuan Chen, Chaosheng Lu, Haiyan Li, Yan Qian, Yi Tan, Huachun Weng, and Lu Cai. Pex11a deficiency causes dyslipidaemia and obesity in mice. Journal of Cellular and Molecular Medicine, 23:2020-2031, Dec 2019. URL: https://doi.org/10.1111/jcmm.14108, doi:10.1111/jcmm.14108. This article has 36 citations and is from a peer-reviewed journal.
(carmichael2022fissionimpossible(?)—new pages 15-16): Ruth E. Carmichael, Markus Islinger, and Michael Schrader. Fission impossible (?)—new insights into disorders of peroxisome dynamics. Cells, 11:1922, Jun 2022. URL: https://doi.org/10.3390/cells11121922, doi:10.3390/cells11121922. This article has 23 citations.
(plessner2024tissuespecificrolesof pages 1-2): Matthias Plessner, Leonie Thiele, Julia Hofhuis, and Sven Thoms. Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, Feb 2024. URL: https://doi.org/10.1186/s13062-024-00458-1, doi:10.1186/s13062-024-00458-1. This article has 5 citations and is from a peer-reviewed journal.
(plessner2024tissuespecificrolesof pages 2-5): Matthias Plessner, Leonie Thiele, Julia Hofhuis, and Sven Thoms. Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, Feb 2024. URL: https://doi.org/10.1186/s13062-024-00458-1, doi:10.1186/s13062-024-00458-1. This article has 5 citations and is from a peer-reviewed journal.
(plessner2024tissuespecificrolesof pages 5-8): Matthias Plessner, Leonie Thiele, Julia Hofhuis, and Sven Thoms. Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, Feb 2024. URL: https://doi.org/10.1186/s13062-024-00458-1, doi:10.1186/s13062-024-00458-1. This article has 5 citations and is from a peer-reviewed journal.
(plessner2024tissuespecificrolesof media 02bf5939): Matthias Plessner, Leonie Thiele, Julia Hofhuis, and Sven Thoms. Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, Feb 2024. URL: https://doi.org/10.1186/s13062-024-00458-1, doi:10.1186/s13062-024-00458-1. This article has 5 citations and is from a peer-reviewed journal.
(plessner2024tissuespecificrolesof media af8b9ce7): Matthias Plessner, Leonie Thiele, Julia Hofhuis, and Sven Thoms. Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, Feb 2024. URL: https://doi.org/10.1186/s13062-024-00458-1, doi:10.1186/s13062-024-00458-1. This article has 5 citations and is from a peer-reviewed journal.
(subramani2023convergentanddivergent pages 7-9): Suresh Subramani, Nandini Shukla, and Jean-Claude Farre. Convergent and divergent mechanisms of peroxisomal and mitochondrial division. The Journal of Cell Biology, Aug 2023. URL: https://doi.org/10.1083/jcb.202304076, doi:10.1083/jcb.202304076. This article has 7 citations.
(plessner2024tissuespecificrolesof pages 8-10): Matthias Plessner, Leonie Thiele, Julia Hofhuis, and Sven Thoms. Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, Feb 2024. URL: https://doi.org/10.1186/s13062-024-00458-1, doi:10.1186/s13062-024-00458-1. This article has 5 citations and is from a peer-reviewed journal.
(li2002pex11αisrequired pages 10-11): Xiaoling Li, Eveline Baumgart, Gao-Xiang Dong, James C. Morrell, Gerardo Jimenez-Sanchez, David Valle, Kirby D. Smith, and Stephen J. Gould. Pex11α is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Molecular and Cellular Biology, 22:8226-8240, Dec 2002. URL: https://doi.org/10.1128/mcb.22.23.8226-8240.2002, doi:10.1128/mcb.22.23.8226-8240.2002. This article has 197 citations and is from a domain leading peer-reviewed journal.
(weng2013pex11αdeficiencyimpairs pages 8-8): Huachun Weng, Xu Ji, Yukiko Naito, Kosuke Endo, Xiao Ma, Rie Takahashi, Chunshen Shen, Go Hirokawa, Yasue Fukushima, and Naoharu Iwai. Pex11α deficiency impairs peroxisome elongation and division and contributes to nonalcoholic fatty liver in mice. American journal of physiology. Endocrinology and metabolism, 304 2:E187-96, Jan 2013. URL: https://doi.org/10.1152/ajpendo.00425.2012, doi:10.1152/ajpendo.00425.2012. This article has 53 citations.
(bonekamp2013selfinteractionofhuman pages 1-3): Nina A. Bonekamp, Sandra Grille, Maria Joao Cardoso, Monica Almeida, Miguel Aroso, Silvia Gomes, Ana Cristina Magalhaes, Daniela Ribeiro, Markus Islinger, and Michael Schrader. Self-interaction of human pex11pβ during peroxisomal growth and division. PLoS ONE, 8:e53424, Jan 2013. URL: https://doi.org/10.1371/journal.pone.0053424, doi:10.1371/journal.pone.0053424. This article has 39 citations and is from a peer-reviewed journal.
id: O75192
gene_symbol: PEX11A
product_type: PROTEIN
status: IN_PROGRESS
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
PEX11A (Peroxisomal membrane protein 11A, also known as PEX11-alpha or PMP28) is an
inducible integral peroxisomal membrane protein that functions as a membrane elongation
factor promoting peroxisome proliferation. It is one of three mammalian PEX11 paralogs
(PEX11A, PEX11B, PEX11G). Unlike the constitutively expressed PEX11B, PEX11A expression
is induced by peroxisome proliferators (e.g., clofibrate, 4-phenylbutyrate) and high-fat
diet. PEX11A homo- and heterodimerizes (with PEX11G) and interacts with the fission
factor FIS1, linking membrane elongation to the DRP1-dependent scission machinery.
PEX11A-null mice show normal baseline peroxisomes but fail to proliferate peroxisomes
in response to 4-PBA, and develop metabolic phenotypes (fatty liver, dyslipidemia)
under dietary stress. No human disease mutations have been described.
alternative_products:
- name: '1'
id: O75192-1
- name: '2'
id: O75192-2
sequence_note: VSP_054753
existing_annotations:
# --- IBA annotations ---
- term:
id: GO:0005778
label: peroxisomal membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
PEX11A is an integral peroxisomal membrane protein with two transmembrane helices,
confirmed by multiple independent experimental studies. IBA annotation is phylogenetically
well-supported across the PEX11 family.
action: ACCEPT
reason: >-
Peroxisomal membrane localization is the most fundamental and well-established aspect
of PEX11A biology. The original cloning paper (PMID:9714566) showed it is an integral
peroxisomal membrane protein. Multiple IDA annotations from PMID:9714566, PMID:9792670,
and PMID:20826455 also confirm this. The IBA annotation is consistent with all evidence.
supported_by:
- reference_id: PMID:9714566
supporting_text: "PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus."
- reference_id: PMID:9792670
supporting_text: "We report here the identification and characterization of two novel human peroxisomal membrane proteins, PEX11alpha and PEX11beta."
- reference_id: file:human/PEX11A/PEX11A-deep-research-falcon.md
supporting_text: "PEX11A is an integral peroxisomal membrane protein that functions as a membrane elongation factor promoting peroxisome proliferation"
- term:
id: GO:0016559
label: peroxisome fission
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
PEX11A promotes peroxisome elongation (formation of juxtaposed elongated peroxisomes, JEPs)
which is a prerequisite step for peroxisome fission/division. IBA annotation is
phylogenetically well-supported across the PEX11 family from yeast to humans.
action: ACCEPT
reason: >-
Peroxisome fission is the core biological process for PEX11 family proteins. Koch et al.
(2010, PMID:20826455) showed that PEX11 family members drive membrane elongation and
coordinate with fission machinery (FIS1, DRP1) for peroxisome division. The IBA reflects
a conserved function across eukaryotes.
supported_by:
- reference_id: PMID:20826455
supporting_text: "Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation."
- reference_id: PMID:20826455
supporting_text: "Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression."
# --- IEA annotations ---
- term:
id: GO:0005778
label: peroxisomal membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: >-
Combined automated annotation for peroxisomal membrane localization. Broader than the
IBA annotation but consistent with extensive experimental evidence.
action: ACCEPT
reason: >-
This IEA annotation is redundant with the IBA and multiple IDA annotations for the
same term, but is not incorrect. PEX11A is unequivocally a peroxisomal membrane protein.
supported_by:
- reference_id: PMID:9714566
supporting_text: "PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus."
- term:
id: GO:0007031
label: peroxisome organization
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: >-
IEA annotation derived from UniProtKB keyword mapping (Peroxisome biogenesis keyword).
Peroxisome organization is a parent term of peroxisome fission. PEX11A is involved in
peroxisome organization via its membrane elongation/fission role.
action: ACCEPT
reason: >-
This is a broader parent term of peroxisome fission (GO:0016559). Since PEX11A is
clearly involved in peroxisome fission, it is also involved in peroxisome organization.
The IEA is consistent with the more specific IDA and IBA annotations for peroxisome fission.
supported_by:
- reference_id: PMID:9792670
supporting_text: "Overexpression of PEX11alpha also induced peroxisome proliferation but at a much lower frequency than PEX11beta in our experimental system."
- term:
id: GO:0016559
label: peroxisome fission
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: >-
IEA annotation from InterPro domain mapping (IPR008733, PEX11 domain). Consistent with
the core function of PEX11 family proteins in peroxisome fission.
action: ACCEPT
reason: >-
The PEX11 domain (IPR008733/PF05648) is specifically associated with peroxisome fission
function. This IEA is consistent with the IBA and IDA annotations for the same term.
supported_by:
- reference_id: PMID:20826455
supporting_text: "Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression."
- term:
id: GO:0016557
label: peroxisome membrane biogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: >-
IEA annotation from Ensembl Compara ortholog transfer (from rat Pex11a, O70597).
PEX11A promotes peroxisomal membrane elongation and contributes to membrane growth
during peroxisome division. However, peroxisome membrane biogenesis specifically
refers to formation of peroxisome membranes, which is more the domain of PEX3/PEX16/PEX19.
action: MARK_AS_OVER_ANNOTATED
reason: >-
PEX11A is a membrane elongation factor that promotes peroxisome division, not a
peroxisome membrane biogenesis factor per se. Peroxisome membrane biogenesis
(GO:0016557) implies de novo formation of peroxisomal membranes, which is more
specifically the role of PEX3, PEX16, and PEX19. PEX11A acts on pre-existing
peroxisomal membranes to promote elongation and division. While there is some
overlap, this term is misleading for PEX11A. The more accurate term is peroxisome
fission (GO:0016559), already annotated.
supported_by:
- reference_id: PMID:9922452
supporting_text: "We propose that peroxisomes may form by either of two pathways: one that involves PEX11-mediated division of preexisting peroxisomes, and another that involves PEX16-mediated formation of peroxisomes in the absence of preexisting peroxisomes."
# --- IDA annotations for localization ---
- term:
id: GO:0005777
label: peroxisome
evidence_type: IDA
original_reference_id: PMID:19114594
review:
summary: >-
In Matsuzaki & Fujiki (2008), PEX11A (as HA-Pex11alpha) was used as a control in
experiments studying Pex3p targeting. The paper confirmed PEX11A localizes to
peroxisomes but PEX11A was not the main subject of study; it was used as a negative
control for Pex16p-mediated Pex3p recruitment.
action: ACCEPT
reason: >-
While PEX11A was not the focus of this paper, it was used as a peroxisomal membrane
marker/control, and its localization to peroxisomes was confirmed by immunofluorescence.
The peroxisome localization annotation is well-supported, though the more specific
peroxisomal membrane (GO:0005778) term is preferable.
supported_by:
- reference_id: PMID:19114594
supporting_text: "We confirmed the complementing activity of PEX14-EGFP, HA-PEX13, HA-PEX12, HA-PEX10, HA-PEX2, and PEX3-Myc, using respective PEX-defective mutants, and the peroxisome division activity of HA-PEX11alpha with wild-type CHO cells."
- term:
id: GO:0005777
label: peroxisome
evidence_type: IDA
original_reference_id: PMID:18782765
review:
summary: >-
In Delille & Schrader (2008), Pex11p-alpha-YFP was used as a peroxisomal membrane
marker in COS-7 cells to specifically label peroxisomes for subcellular fractionation
experiments studying hFis1 targeting. The paper confirmed peroxisomal localization
of Pex11p-alpha.
action: ACCEPT
reason: >-
PEX11A-YFP was explicitly shown to localize to peroxisomes by immunofluorescence.
This is a well-supported localization annotation, though the more specific
peroxisomal membrane (GO:0005778) is preferable.
supported_by:
- reference_id: PMID:18782765
supporting_text: "Pex11pα-YFP, which exposes its N and C termini toward the cytosol ( 53 ), localized specifically to peroxisomes ( Fig"
- reference_id: PMID:18782765
supporting_text: "In contrast to other peroxisomal membrane proteins (for example, Pex11pβ) ( 46 ), no morphological alterations of the peroxisomal compartment were induced by Pex11pα-YFP, which might have influenced the association of hFis1 ( Fig"
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20826455
review:
summary: >-
PEX11A was shown to interact with FIS1 (UniProtKB:Q9Y3D6) and PEX11G (UniProtKB:Q96HA9)
by co-immunoprecipitation in Koch et al. (2010). However, 'protein binding' (GO:0005515)
is too vague to be informative. The GOA file shows two separate IPI entries for this
term, one for FIS1 and one for PEX11G. The interactions are functionally relevant:
PEX11A-FIS1 interaction links membrane elongation to fission machinery recruitment,
and PEX11A-PEX11G heterodimerization is part of the oligomerization required for function.
action: REMOVE
reason: >-
Per curation guidelines, 'protein binding' (GO:0005515) is uninformative and should be
avoided. The specific interactions with FIS1 and PEX11G are better captured by the
homodimerization activity annotation (GO:0042803) and the protein-containing complex
annotation (GO:0032991). The functional significance is already captured by the
peroxisome fission annotation (GO:0016559).
supported_by:
- reference_id: PMID:20826455
supporting_text: "We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1"
- term:
id: GO:0005777
label: peroxisome
evidence_type: IDA
original_reference_id: PMID:20826455
review:
summary: >-
Koch et al. (2010) showed PEX11A localizes to peroxisomes by fluorescence microscopy.
This is the most comprehensive study of PEX11 family function.
action: ACCEPT
reason: >-
Peroxisome localization is core to PEX11A function and well-supported by this study.
The more specific term peroxisomal membrane (GO:0005778) is also annotated separately.
supported_by:
- reference_id: PMID:20826455
supporting_text: "Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation."
- term:
id: GO:0016559
label: peroxisome fission
evidence_type: IDA
original_reference_id: PMID:20826455
review:
summary: >-
Koch et al. (2010) demonstrated that PEX11 family members (including PEX11A) are
membrane elongation factors that coordinate peroxisome proliferation. Overexpression
leads to juxtaposed elongated peroxisomes (JEPs), which represent intermediates in
peroxisome division. Excess FIS1 can resolve JEPs into normal round peroxisomes,
demonstrating the elongation-to-fission pathway.
action: ACCEPT
reason: >-
This is the key experimental paper establishing PEX11 proteins as membrane elongation
factors coordinating peroxisome fission. The IDA evidence is strong and directly
supports this core function annotation.
supported_by:
- reference_id: PMID:20826455
supporting_text: "Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression."
- reference_id: PMID:20826455
supporting_text: "We show that excess of hFis1 but not of DRP1 is sufficient to fragment JEPs into normal round-shaped organelles"
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:20826455
review:
summary: >-
Koch et al. (2010) demonstrated that PEX11A forms homodimers and heterodimers with
PEX11G, and interacts with FIS1. The protein-containing complex annotation reflects
these oligomerization properties. However, GO:0032991 is extremely generic.
action: ACCEPT
reason: >-
PEX11A demonstrably forms homo- and heterodimeric complexes (with PEX11G) and interacts
with FIS1 as part of the fission machinery. While the term is generic, it accurately
reflects the oligomeric nature of PEX11A. A more specific complex term would be preferable
but none exists in GO for the PEX11 complex.
supported_by:
- reference_id: PMID:20826455
supporting_text: "We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1"
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: IDA
original_reference_id: PMID:20826455
review:
summary: >-
Koch et al. (2010) demonstrated PEX11A homodimerization by co-immunoprecipitation
and showed that the C-terminal transmembrane domain (region 220-239) is required for
homodimerization. Homodimerization is important for PEX11A membrane-shaping function.
action: ACCEPT
reason: >-
Homodimerization was directly demonstrated experimentally and is functionally important
for PEX11A's membrane elongation activity. This is a well-supported molecular function
annotation. UniProt also notes that region 220-239 is required for homodimerization.
supported_by:
- reference_id: PMID:20826455
supporting_text: "We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1"
- term:
id: GO:0044375
label: regulation of peroxisome size
evidence_type: IDA
original_reference_id: PMID:20826455
review:
summary: >-
Koch et al. (2010) showed that overexpression of PEX11 family members leads to elongated
peroxisomes (JEPs), directly demonstrating regulation of peroxisome morphology and size.
This annotation captures the membrane remodeling aspect of PEX11A function.
action: ACCEPT
reason: >-
PEX11A overexpression leads to elongated peroxisomes, directly demonstrating its role
in regulating peroxisome size/morphology. This complements the peroxisome fission
annotation by capturing the upstream membrane remodeling step.
supported_by:
- reference_id: PMID:20826455
supporting_text: "Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation."
- term:
id: GO:0005778
label: peroxisomal membrane
evidence_type: IDA
original_reference_id: PMID:9792670
review:
summary: >-
Schrader et al. (1998) identified PEX11alpha and PEX11beta as novel human peroxisomal
membrane proteins. PEX11alpha was characterized as a peroxisomal membrane protein whose
expression is induced by peroxisome proliferators.
action: ACCEPT
reason: >-
This is one of the original papers characterizing PEX11A as a peroxisomal membrane
protein. The peroxisomal membrane localization is directly demonstrated.
supported_by:
- reference_id: PMID:9792670
supporting_text: "We report here the identification and characterization of two novel human peroxisomal membrane proteins, PEX11alpha and PEX11beta."
- term:
id: GO:0005778
label: peroxisomal membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1989753
review:
summary: >-
Reactome entry R-HSA-1989753 describes the expression of PEX11A as part of the
PPARA activates gene expression pathway. The TAS annotation for peroxisomal membrane
localization is consistent with all experimental evidence.
action: ACCEPT
reason: >-
The Reactome annotation correctly places PEX11A at the peroxisomal membrane. While
the Reactome entry itself is minimal (just transcription/translation of PEX11A gene),
the localization is well-established by multiple other sources.
supported_by:
- reference_id: PMID:9714566
supporting_text: "PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus."
- term:
id: GO:0005778
label: peroxisomal membrane
evidence_type: IDA
original_reference_id: PMID:9714566
review:
summary: >-
Abe et al. (1998) cloned human PEX11 cDNA and showed it encodes a 28 kDa peroxisomal
integral membrane protein (PMP28) with two transmembrane segments. Topology studies
showed both N- and C-terminal parts are exposed to the cytosol. The protein was shown
to be the clofibrate-inducible PMP28 previously identified from rat liver.
action: ACCEPT
reason: >-
This is the original cloning and characterization paper for human PEX11A. It provides
direct experimental evidence for peroxisomal membrane localization including topology
mapping, co-migration with PMP28, and immunoreactivity with anti-PMP28 antibodies.
supported_by:
- reference_id: PMID:9714566
supporting_text: "PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus."
- reference_id: PMID:9714566
supporting_text: "Pex11p exposes both N- and C-terminal parts to the cytosol."
- term:
id: GO:0007031
label: peroxisome organization
evidence_type: IMP
original_reference_id: PMID:9792670
review:
summary: >-
Schrader et al. (1998) showed that overexpression of PEX11alpha induced peroxisome
proliferation through a multistep process involving peroxisome elongation and division.
PEX11alpha mRNA was induced more than 10-fold by peroxisome proliferators clofibrate
and DEHP, suggesting a role in regulated peroxisome organization.
action: ACCEPT
reason: >-
The IMP evidence from overexpression studies directly shows PEX11A involvement in
peroxisome organization. This is a parent term of peroxisome fission, and the annotation
is well-supported by the observed peroxisome proliferation phenotype upon overexpression.
supported_by:
- reference_id: PMID:9792670
supporting_text: "Overexpression of PEX11alpha also induced peroxisome proliferation but at a much lower frequency than PEX11beta in our experimental system."
- reference_id: PMID:9792670
supporting_text: "PEX11alpha mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents, and were induced more than 10-fold in response to the peroxisome proliferators clofibrate and di(2-ethylhexyl) phthalate."
- term:
id: GO:0007165
label: signal transduction
evidence_type: IMP
original_reference_id: PMID:9792670
review:
summary: >-
This annotation to signal transduction (GO:0007165) is based on the observation that
PEX11alpha is transcriptionally induced by peroxisome proliferators (clofibrate, DEHP)
and that its mRNA levels are highest in tissues sensitive to these agents. However,
PEX11A itself is not a signaling molecule -- it is a downstream effector of the
PPARalpha signaling pathway. Being transcriptionally regulated by a signal does not
make PEX11A "involved in" signal transduction.
action: REMOVE
reason: >-
PEX11A is a target gene of PPARalpha-mediated signaling, not a component of the signal
transduction machinery itself. The fact that PEX11A expression is induced by peroxisome
proliferators reflects its regulation by the PPARalpha pathway, but PEX11A does not
transduce signals. This is an over-annotation arising from conflating transcriptional
response to a signal with participation in signal transduction. Signal transduction
(GO:0007165) should be reserved for molecules that directly participate in signaling
cascades (receptors, kinases, transcription factors, etc.), not their downstream
structural/enzymatic targets.
supported_by:
- reference_id: PMID:9792670
supporting_text: "PEX11alpha mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents, and were induced more than 10-fold in response to the peroxisome proliferators clofibrate and di(2-ethylhexyl) phthalate."
- term:
id: GO:0005777
label: peroxisome
evidence_type: IDA
original_reference_id: PMID:9922452
review:
summary: >-
In South & Gould (1999), PEX11alpha-myc was expressed in PBD061 cells (PEX16-deficient)
and control PBD094 cells as one of many PMPs tested for import. PEX11alpha-myc was
used as a peroxisomal membrane protein marker. The paper is primarily about PEX16
and de novo peroxisome formation, not about PEX11A function.
action: ACCEPT
reason: >-
While PEX11A was not the focus of this study, it was used as a known peroxisomal membrane
protein and its localization to peroxisomes was confirmed. The annotation is correct.
supported_by:
- reference_id: PMID:9922452
supporting_text: "Similar results were observed in cells transfected with expression vectors designed to express other human PMPs, including PEX3myc (Kammerer et al., 1998), PEX10myc (Warren et al., 1998), PEX11αmyc (Schrader et al., 1998), PEX11βmyc (Schrader et al., 1998), and PEX13myc (Gould et al., 1996) (data not shown)"
# --- Proposed new annotations ---
- term:
id: GO:0046982
label: protein heterodimerization activity
evidence_type: IDA
original_reference_id: PMID:20826455
review:
summary: >-
Koch et al. (2010) demonstrated that PEX11A forms heterodimers with PEX11G in addition
to homodimers. This heterodimerization activity is functionally significant for
coordinating peroxisome proliferation. The homodimerization activity is already annotated
(GO:0042803) but the heterodimerization with PEX11G is not captured.
action: NEW
reason: >-
PEX11A-PEX11G heterodimerization was directly demonstrated by Koch et al. (2010) and
is an important aspect of PEX11A molecular function not currently captured by existing
annotations. UniProt also states PEX11A is a heterodimer with PEX11G.
supported_by:
- reference_id: PMID:20826455
supporting_text: "We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1"
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:18782765
title: Targeting of hFis1 to peroxisomes is mediated by Pex19p.
findings:
- statement: PEX11A-YFP was used as a peroxisomal membrane marker in COS-7 cells, confirming its peroxisomal localization.
supporting_text: "Pex11pα-YFP, which exposes its N and C termini toward the cytosol ( 53 ), localized specifically to peroxisomes ( Fig"
- statement: PEX11A-YFP did not induce morphological alterations of peroxisomes, unlike PEX11B, consistent with its lower basal activity.
supporting_text: "In contrast to other peroxisomal membrane proteins (for example, Pex11pβ) ( 46 ), no morphological alterations of the peroxisomal compartment were induced by Pex11pα-YFP, which might have influenced the association of hFis1 ( Fig"
- id: PMID:19114594
title: The peroxisomal membrane protein import receptor Pex3p is directly transported
to peroxisomes by a novel Pex19p- and Pex16p-dependent pathway.
findings:
- statement: HA-PEX11alpha was used as a control in Pex16p knockdown experiments and was correctly targeted to peroxisomes even when Pex3p was misdirected.
supporting_text: "We confirmed the complementing activity of PEX14-EGFP, HA-PEX13, HA-PEX12, HA-PEX10, HA-PEX2, and PEX3-Myc, using respective PEX-defective mutants, and the peroxisome division activity of HA-PEX11alpha with wild-type CHO cells."
- statement: PEX11A served as negative control for Pex16p-mediated Pex3p recruitment, showing its targeting is independent of Pex16p.
supporting_text: "We confirmed the complementing activity of PEX14-EGFP, HA-PEX13, HA-PEX12, HA-PEX10, HA-PEX2, and PEX3-Myc, using respective PEX-defective mutants, and the peroxisome division activity of HA-PEX11alpha with wild-type CHO cells."
- id: PMID:20826455
title: PEX11 family members are membrane elongation factors that coordinate peroxisome
proliferation and maintenance.
findings:
- statement: PEX11 family members (including PEX11A) are membrane elongation factors that drive formation of juxtaposed elongated peroxisomes (JEPs).
supporting_text: "Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation."
- statement: PEX11A homo- and heterodimerizes (with PEX11G) and interacts with FIS1.
supporting_text: "We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1"
- statement: JEPs are intermediates in peroxisome membrane proliferation; FIS1 is the limiting factor for progression to fission.
supporting_text: "Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression."
- statement: Excess FIS1 but not DRP1 is sufficient to resolve JEPs into round organelles.
supporting_text: "We show that excess of hFis1 but not of DRP1 is sufficient to fragment JEPs into normal round-shaped organelles"
- statement: Microtubules are required for JEP formation.
supporting_text: "We show that excess of hFis1 but not of DRP1 is sufficient to fragment JEPs into normal round-shaped organelles, and illustrate the requirement of microtubules for JEP formation."
- id: PMID:9714566
title: Clofibrate-inducible, 28-kDa peroxisomal integral membrane protein is encoded
by PEX11.
findings:
- statement: Human PEX11 (PEX11A) encodes a 247 amino acid peroxisomal integral membrane protein with two transmembrane segments.
supporting_text: "PEX11 encoded a peroxisomal protein Pex11p comprising 247 amino acids, with two transmembrane segments and a dilysine motif at the C-terminus."
- statement: PEX11A is identical to the clofibrate-inducible 28 kDa peroxisomal integral membrane protein (PMP28).
supporting_text: "Pex11p comigrated in SDS-PAGE with a 28-kDa peroxisomal integral membrane protein (PMP28) isolated from the liver of clofibrate-treated rats and was crossreactive to anti-PMP28 antibody, thereby indicating PEX11 to encode PMP28."
- statement: N- and C-terminal parts are exposed to the cytosol.
supporting_text: "Pex11p exposes both N- and C-terminal parts to the cytosol."
- statement: PEX11 was not responsible for any of ten tested complementation groups of peroxisome deficiency disorders.
supporting_text: "PEX11 was not responsible for ten complementation groups of human peroxisome deficiency disorders."
- id: PMID:9792670
title: Expression of PEX11beta mediates peroxisome proliferation in the absence
of extracellular stimuli.
findings:
- statement: PEX11alpha overexpression induces peroxisome proliferation but at lower frequency than PEX11beta.
supporting_text: "Overexpression of PEX11alpha also induced peroxisome proliferation but at a much lower frequency than PEX11beta in our experimental system."
- statement: PEX11alpha mRNA is induced more than 10-fold by peroxisome proliferators clofibrate and DEHP.
supporting_text: "PEX11alpha mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents, and were induced more than 10-fold in response to the peroxisome proliferators clofibrate and di(2-ethylhexyl) phthalate."
- statement: PEX11alpha mRNA levels are highest in tissues sensitive to peroxisome-proliferating agents.
supporting_text: "PEX11alpha mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents"
- statement: PEX11beta is constitutively expressed while PEX11alpha is inducible.
supporting_text: "Overexpression of the human PEX11beta gene alone was sufficient to induce peroxisome proliferation, demonstrating that proliferation can occur in the absence of extracellular stimuli and may be mediated by a single gene."
- id: PMID:9922452
title: Peroxisome synthesis in the absence of preexisting peroxisomes.
findings:
- statement: PEX11alpha-myc was used as a peroxisomal membrane protein marker in PEX16-deficient cell studies.
supporting_text: "Similar results were observed in cells transfected with expression vectors designed to express other human PMPs, including PEX3myc (Kammerer et al., 1998), PEX10myc (Warren et al., 1998), PEX11αmyc (Schrader et al., 1998), PEX11βmyc (Schrader et al., 1998), and PEX13myc (Gould et al., 1996) (data not shown)"
- statement: Two pathways proposed for peroxisome formation - PEX11-mediated division of pre-existing peroxisomes and PEX16-mediated de novo formation.
supporting_text: "We propose that peroxisomes may form by either of two pathways: one that involves PEX11-mediated division of preexisting peroxisomes, and another that involves PEX16-mediated formation of peroxisomes in the absence of preexisting peroxisomes."
- id: Reactome:R-HSA-1989753
title: Expression of PEX11A
findings:
- statement: PEX11A gene is transcribed and translated as part of PPARA-activated gene expression pathway.
supporting_text: "The PEX11A gene is transcribed to yield mRNA and the mRNA is translated to yield protein."
core_functions:
- description: >-
PEX11A is an inducible membrane elongation factor that promotes peroxisome elongation
as the first step in peroxisome division. It homodimerizes and heterodimerizes with
PEX11G, and interacts with FIS1 to coordinate membrane elongation with DRP1-dependent
scission. Overexpression leads to JEPs (juxtaposed elongated peroxisomes) which are
resolved into daughter peroxisomes by FIS1/DRP1 fission machinery. This is the core
conserved function of the PEX11 family.
molecular_function:
id: GO:0042803
label: protein homodimerization activity
directly_involved_in:
- id: GO:0016559
label: peroxisome fission
- id: GO:0044375
label: regulation of peroxisome size
locations:
- id: GO:0005778
label: peroxisomal membrane
supported_by:
- reference_id: PMID:20826455
supporting_text: "Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression."
- reference_id: PMID:9792670
supporting_text: "Overexpression of PEX11alpha also induced peroxisome proliferation but at a much lower frequency than PEX11beta in our experimental system."