ARL6IP1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016020 membrane	IBA GO_REF:0000033	ACCEPT	Summary: ARL6IP1 is a multi-pass membrane protein localized to ER membranes. This general annotation is correct but uninformative given more specific localizations available. Reason: The annotation is technically correct - ARL6IP1 is indeed a membrane protein with multiple transmembrane domains (PMID:24262037). However, more specific terms like "endoplasmic reticulum membrane" or "endoplasmic reticulum tubular network" better capture its localization. Supporting Evidence: PMID:24262037 Arl6IP1, which does not share an overall primary sequence homology with reticulons, harbours reticulon-like short hairpin transmembrane domains and binds to atlastin, a GTPase that mediates the formation of the tubular ER network
GO:0005784 Sec61 translocon complex	IBA GO_REF:0000033	REMOVE	Summary: This IBA annotation suggests ARL6IP1 is part of the Sec61 translocon complex. However, the deep research and primary literature focus entirely on its role as an ER membrane-shaping protein with reticulon-like function, not as a translocon component. Reason: There is no evidence in the literature that ARL6IP1 is a component of the Sec61 translocon complex. The deep research review (Dong et al. 2018, Yamamoto et al. 2014, Hubner & Kurth 2014) consistently describes ARL6IP1 as an ER membrane-shaping protein that promotes tubular ER formation through reticulon-like hairpin domains. It interacts with atlastin (ATL1) and INPP5K, not with Sec61 components. This IBA annotation appears to be an error in phylogenetic inference, possibly confounding ARL6IP1 with structurally distinct ER proteins.
GO:0006613 cotranslational protein targeting to membrane	IBA GO_REF:0000033	REMOVE	Summary: This IBA annotation suggests involvement in cotranslational protein targeting. However, all primary literature describes ARL6IP1 as an ER membrane-shaping protein, not involved in protein translocation. Reason: No evidence supports a role for ARL6IP1 in cotranslational protein targeting. The established function is ER membrane morphology through reticulon-like curvature induction (PMID:24262037). This annotation likely arose from the same erroneous phylogenetic inference as the Sec61 annotation. ARL6IP1 binds atlastin (a membrane fusion GTPase) and INPP5K (an inositol phosphatase), not ribosome-translocon machinery.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: ARL6IP1 localizes to the endoplasmic reticulum. This is well-supported by multiple experimental studies. Reason: ER localization is extensively documented. Yamamoto et al. 2014 showed ARL6IP1 localizes to ER tubules and sheet edges. Lui et al. 2003 identified it as an ER integral membrane protein. The deep research confirms enrichment on tubular ER. Supporting Evidence: PMID:24262037 Arl6IP1 has the ability to shape high-curvature ER tubules in a reticulon-like fashion PMID:12754298 We demonstrate that ARMER is an endoplasmic reticulum (ER) integral membrane protein
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: ARL6IP1 is an integral ER membrane protein. This core localization is well-supported. Reason: Multiple experimental studies confirm ER membrane localization (PMID:24262037, PMID:12754298). The protein preferentially localizes to ER tubules and sheet edges characterized by high membrane curvature. Supporting Evidence: PMID:24262037 Arl6IP1, which does not share an overall primary sequence homology with reticulons, harbours reticulon-like short hairpin transmembrane domains and binds to atlastin, a GTPase that mediates the formation of the tubular ER network
GO:0006915 apoptotic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This IEA annotation maps from the UniProt "Apoptosis" keyword based on the ARMER name and early characterization. However, the anti-apoptotic effect is a secondary consequence of ER membrane homeostasis, not a direct apoptosis regulatory function. Reason: While ARL6IP1 overexpression does protect cells from apoptosis (PMID:12754298), the deep research makes clear this is secondary to its primary role in ER morphology. Loss of ARL6IP1 causes ER structure disruption, leading to ER stress and cell death as a downstream consequence. The anti-apoptotic effect reflects the importance of proper ER structure for cell viability, not an evolved apoptosis regulatory function. ARL6IP1 is linked to hereditary spastic paraplegia (HSP) via ER dysfunction, not apoptosis dysregulation. The annotation to "apoptotic process" without qualifier is misleading about the protein's core function. Supporting Evidence: PMID:24262037 In the present paper we report that Arl6IP1(ADP-ribosylation factor-like 6 interacting protein 1), an anti-apoptotic protein specific to multicellular organisms, is a potential player in shaping the ER tubules in mammalian cells file:human/ARL6IP1/ARL6IP1-deep-research-falcon.md [Deep research review indicates] ARL6IP1 is named ARMER... but current evidence strongly implicates its primary role in ER membrane shaping
GO:0012505 endomembrane system	IEA GO_REF:0000044	ACCEPT	Summary: ARL6IP1 localizes to the endomembrane system (specifically the ER). This is correct but less informative than more specific terms. Reason: As an ER membrane protein, ARL6IP1 is part of the endomembrane system. More specific terms (ER membrane, ER tubular network) better capture its localization.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	REMOVE	Summary: High-throughput protein-protein interaction study. Generic "protein binding" annotation is uninformative. Reason: "Protein binding" is too vague to be informative about ARL6IP1 function. This annotation from a high-throughput interactome mapping study (Rual et al. 2005) does not specify the binding partner or functional context. More specific interaction terms should be used where biologically meaningful interactions exist. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:19060904 An empirical framework for binary interactome mapping.	REMOVE	Summary: High-throughput interaction study; generic protein binding annotation. Reason: "Protein binding" is uninformative. This high-throughput study does not provide functional context for the interaction. Supporting Evidence: PMID:19060904 An empirical framework for binary interactome mapping.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	REMOVE	Summary: High-throughput interactome study; generic protein binding. Reason: Generic "protein binding" annotation lacks functional specificity. Does not inform about ARL6IP1's molecular function. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: Proteome-scale human interactome network study. Generic protein binding from high-throughput data. Reason: "Protein binding" is uninformative. While ARL6IP1 does interact with specific proteins (ATL1, INPP5K, TMEM33, RTN4), the generic term does not capture these functionally relevant interactions. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	REMOVE	Summary: Study on macromolecular interaction perturbations in genetic disorders. Reason: Generic protein binding annotation is uninformative. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	REMOVE	Summary: Alternative splicing and protein interaction capabilities study. Reason: Generic protein binding annotation lacks functional specificity. Supporting Evidence: PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
GO:0005515 protein binding	IPI PMID:27107014 An inter-species protein-protein interaction network across ...	REMOVE	Summary: Inter-species protein-protein interaction network study. Reason: Generic protein binding annotation is uninformative. Supporting Evidence: PMID:27107014 An inter-species protein-protein interaction network across vast evolutionary distance.
GO:0005515 protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	REMOVE	Summary: Interactome perturbation study for developmental disorders. Reason: Generic protein binding annotation lacks functional context. Supporting Evidence: PMID:29892012 Jun 11. An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	REMOVE	Summary: Study on protein interaction disruption by genetic variants. Reason: Generic protein binding annotation is uninformative. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Reference human binary protein interactome map. Reason: Generic "protein binding" annotation is uninformative. For functionally important interactions like ATL1, INPP5K, or RTN4 binding, more specific annotations should be used. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Cell-specific interactome remodeling study. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome.	REMOVE	Summary: SARS-CoV-2 contactome study showing interaction with viral protein. Reason: Generic protein binding to a viral protein (SARS-CoV-2 ORF6) does not inform about normal ARL6IP1 function. This is likely a consequence of ER localization rather than a biologically meaningful interaction for ARL6IP1 function. Supporting Evidence: PMID:36217029 2022 Oct 10. A proteome-scale map of the SARS-CoV-2-human contactome.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	ACCEPT	Summary: ARL6IP1 forms homooligomers. This is consistent with other ER-shaping proteins like reticulons that oligomerize to generate membrane curvature. Reason: ARL6IP1 homooligomerization is documented in UniProt (from PMID:24262037) and is consistent with its reticulon-like membrane-shaping function. ER-shaping proteins typically oligomerize to effectively generate membrane curvature. Supporting Evidence: PMID:24262037 Arl6IP1 has the ability to shape high-curvature ER tubules in a reticulon-like fashion PMID:25416956 A proteome-scale map of the human interactome network.
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	ACCEPT	Summary: Self-interaction/homooligomerization confirmed in interactome study. Reason: Confirms homooligomerization, which is functionally relevant for ER membrane shaping. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0002038 positive regulation of L-glutamate import across plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is transferred from mouse ortholog based on experimental evidence that ARL6IP1 positively regulates SLC1A1/EAAC1-mediated glutamate transport. Reason: UniProt documents that ARL6IP1 positively regulates glutamate transport by increasing SLC1A1/EAAC1 affinity for glutamate, possibly by reducing interaction with ARL6IP5 (a negative regulator). However, this is not the core function of ARL6IP1. The primary function is ER membrane shaping. Glutamate transport regulation may be a secondary effect or specific to certain cellular contexts.
GO:0005737 cytoplasm	IEA GO_REF:0000107	MODIFY	Summary: Cytoplasm localization is too general. ARL6IP1 is an ER membrane protein with cytoplasmic domains but is not a cytoplasmic protein per se. Reason: ARL6IP1 is an integral ER membrane protein. While it has cytoplasmic domains (N- and C-termini are cytoplasmic), the protein is membrane-associated, not free in cytoplasm. More specific ER-related localization terms are appropriate. Proposed replacements: endoplasmic reticulum membrane
GO:0005784 Sec61 translocon complex	IEA GO_REF:0000107	REMOVE	Summary: IEA annotation suggesting Sec61 translocon complex localization. No literature supports this. Reason: There is no evidence that ARL6IP1 localizes to or is part of the Sec61 translocon complex. All functional evidence points to its role as an ER membrane-shaping protein that localizes to tubular ER and sheet edges, interacting with atlastin and INPP5K, not translocon machinery.
GO:0005829 cytosol	IEA GO_REF:0000107	REMOVE	Summary: Cytosol localization is incorrect for an integral ER membrane protein. Reason: ARL6IP1 is an integral ER membrane protein with multiple transmembrane domains. It is not a cytosolic protein. The cytoplasmic portions are domains of the membrane-embedded protein, not free cytosolic protein.
GO:0016020 membrane	IEA GO_REF:0000107	ACCEPT	Summary: General membrane localization annotation; correct but uninformative. Reason: Correct but superseded by more specific ER membrane annotations.
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: IDA from immunofluorescence data (HPA) confirming ER localization. Reason: Experimental confirmation of ER localization is well-supported by multiple studies including the primary literature on ARL6IP1 function. Supporting Evidence: PMID:24262037 Arl6IP1 has the ability to shape high-curvature ER tubules
GO:0071782 endoplasmic reticulum tubular network	IDA PMID:35346366 Liver X receptor-agonist treatment rescues degeneration in a...	ACCEPT	Summary: ARL6IP1 localizes to the ER tubular network. This is highly consistent with its established function as an ER membrane-shaping protein that promotes tubular ER. Reason: This is a core localization for ARL6IP1. The deep research extensively documents ARL6IP1 enrichment on tubular ER, particularly in peripheral/newly formed ER tubules. Depletion causes shift to ER sheets. Supporting Evidence: PMID:24262037 Arl6IP1 has the ability to shape high-curvature ER tubules in a reticulon-like fashion PMID:35346366 Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia.
GO:0005789 endoplasmic reticulum membrane	IDA PMID:24262037 Arl6IP1 has the ability to shape the mammalian ER membrane i...	ACCEPT	Summary: Experimental demonstration of ER membrane localization from the primary study characterizing ARL6IP1's membrane-shaping function. Reason: Yamamoto et al. 2014 demonstrated ARL6IP1 is an ER membrane protein with reticulon-like hairpin domains that preferentially localizes to ER tubules and sheet edges. Supporting Evidence: PMID:24262037 Arl6IP1, which does not share an overall primary sequence homology with reticulons, harbours reticulon-like short hairpin transmembrane domains and binds to atlastin, a GTPase that mediates the formation of the tubular ER network
GO:1903371 regulation of endoplasmic reticulum tubular network organization	IMP PMID:24262037 Arl6IP1 has the ability to shape the mammalian ER membrane i...	ACCEPT	Summary: IMP evidence showing ARL6IP1 regulates ER tubular network organization. This is a core function. Reason: Yamamoto et al. 2014 demonstrated through mutant phenotype analysis that ARL6IP1 overexpression induces extensive ER tubules and stabilizes them even in absence of microtubules. Depletion shifts ER toward sheets. This is a core function. Supporting Evidence: PMID:24262037 Overexpression of Arl6IP1 induced extensive tubular structures of the ER and excluded a luminal protein. Furthermore, overexpression of Arl6IP1 stabilized the ER tubules
GO:0002038 positive regulation of L-glutamate import across plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse ortholog for glutamate transport regulation. Reason: While documented in UniProt, glutamate transport regulation is not the core function of ARL6IP1. The primary function is ER membrane shaping. This may represent a secondary or context-specific function.
GO:0005515 protein binding	IPI PMID:24262037 Arl6IP1 has the ability to shape the mammalian ER membrane i...	ACCEPT	Summary: From the primary ARL6IP1 characterization study showing interaction with ATL1 (atlastin). This is a functionally meaningful interaction. Reason: This annotation captures the interaction with ATL1 (atlastin), which is functionally important for ER tubule formation. While "protein binding" is generic, this specific interaction is documented in the primary literature. Supporting Evidence: PMID:24262037 binds to atlastin, a GTPase that mediates the formation of the tubular ER network
GO:0005789 endoplasmic reticulum membrane	IDA PMID:12754298 ARMER, apoptotic regulator in the membrane of the endoplasmi...	ACCEPT	Summary: The original ARMER paper demonstrating ER membrane localization. Reason: Lui et al. 2003 demonstrated that ARL6IP1/ARMER is an ER integral membrane protein with four predicted transmembrane domains. Supporting Evidence: PMID:12754298 We demonstrate that ARMER is an endoplasmic reticulum (ER) integral membrane protein with four predicted transmembrane domains
GO:0043066 negative regulation of apoptotic process	IDA PMID:12754298 ARMER, apoptotic regulator in the membrane of the endoplasmi...	KEEP AS NON CORE	Summary: IDA evidence from Lui et al. 2003 showing ARL6IP1 overexpression protects cells from apoptosis by inhibiting caspase-9 activity. However, this is a secondary effect of its ER homeostasis function. Reason: The experimental evidence that ARL6IP1 overexpression protects from apoptosis is valid (PMID:12754298). However, the deep research makes clear this anti-apoptotic effect is secondary to its primary role in ER membrane shaping. Loss of ER-shaping proteins causes ER stress and downstream cell death. The anti-apoptotic effect reflects the importance of proper ER structure for cell viability. ARL6IP1 is linked to HSP via ER dysfunction, not apoptosis pathway dysregulation. Keep as non-core to acknowledge the experimental observation while not misrepresenting ARL6IP1's primary function. Supporting Evidence: PMID:12754298 Cells in which ARMER was overexpressed exhibited protection from multiple apoptotic inducers including serum starvation, doxorubicin, UV irradiation, tumor necrosis factor alpha, and the ER stressors PMID:24262037 In the present paper we report that Arl6IP1(ADP-ribosylation factor-like 6 interacting protein 1), an anti-apoptotic protein specific to multicellular organisms, is a potential player in shaping the ER tubules in mammalian cells
GO:0071787 endoplasmic reticulum tubular network formation	IDA PMID:24262037 Arl6IP1 has the ability to shape the mammalian ER membrane i...	ACCEPT	Summary: IDA evidence for ARL6IP1 role in ER tubular network formation. This is a core function. Reason: Yamamoto et al. 2014 directly demonstrated that ARL6IP1 induces ER tubule formation through reticulon-like membrane curvature activity. Overexpression induced extensive ER tubules; the hairpin transmembrane domains are required for this activity. Supporting Evidence: PMID:24262037 Overexpression of Arl6IP1 induced extensive tubular structures of the ER... Arl6IP1 constricted liposomes into tubules. The short hairpin structures of the transmembrane domains were required for the membrane-shaping activity
GO:1990809 endoplasmic reticulum tubular network membrane organization	IDA PMID:24262037 Arl6IP1 has the ability to shape the mammalian ER membrane i...	ACCEPT	Summary: IDA evidence for ARL6IP1 role in ER tubular network membrane organization. Core function. Reason: This annotation captures ARL6IP1's core function in organizing ER tubular membranes through reticulon-like curvature induction. Supporting Evidence: PMID:24262037 Arl6IP1 has the ability to shape high-curvature ER tubules in a reticulon-like fashion
GO:0005515 protein binding	IPI PMID:25612671 Identification and characterization of TMEM33 as a reticulon...	ACCEPT	Summary: Interaction with TMEM33 (a reticulon-binding protein) identified by Urade et al. 2014. This is a functionally relevant interaction in the context of ER membrane organization. Reason: TMEM33 binding is documented in UniProt. As a reticulon-binding protein, TMEM33 interaction with the reticulon-like ARL6IP1 is functionally coherent with ER membrane organization. Supporting Evidence: PMID:25612671 Identification and characterization of TMEM33 as a reticulon-binding protein.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: High-throughput data analysis from NK cell membrane proteome study. Reason: Membrane localization is correct, though less specific than ER membrane terms. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells.

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