PNPT1 encodes polynucleotide phosphorylase (PNPase), a nuclear-encoded mitochondrial 3'-to-5' exoribonuclease of the RNase PH family. PNPase forms a homotrimeric ring built from two RNase PH domains per protomer, with KH and S1 RNA-binding domains forming the central channel, and catalyses processive phosphorolysis of RNA (releasing nucleoside diphosphates) as well as the reverse, template-independent polymerisation reaction. Two PNPase-containing pools have been described in mitochondria: a bulk pool reported in the intermembrane space, and a matrix pool that associates with the RNA helicase SUV3 (SUPV3L1) to form the mitochondrial RNA degradosome (a 330-kDa heteropentamer of a PNPase trimer and an SUV3 dimer). The degradosome acts in foci near nucleoids to degrade structured and double-stranded mitochondrial transcripts, particularly light-strand antisense and non-coding RNAs, G-quadruplex-containing RNAs (with GRSF1) and 5-methylcytosine-marked transcripts (recruited by C1QBP). By restricting mitochondrial double-stranded RNA, PNPase prevents its release to the cytosol and activation of an MDA5-dependent type I interferon response. PNPase has also been implicated in import of small nuclear-encoded RNAs (5S rRNA, RNase P and MRP RNAs) into mitochondria and in shaping mitochondrial mRNA 3' ends and poly(A) tails; it is interferon-inducible, and when overexpressed it can degrade cytoplasmic RNAs such as c-myc mRNA and miR-221. Biallelic hypomorphic PNPT1 variants cause combined oxidative phosphorylation deficiency 13 (encephalomyopathy with respiratory-chain defects and interferon activation) and autosomal recessive nonsyndromic hearing loss.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000175 3'-5'-RNA exonuclease activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA 3'-5'-RNA exonuclease activity for the PNPase family. Reason: PNPase is a processive 3'-to-5' exoribonuclease (phosphorolytic); the activity is demonstrated for the purified human enzyme. Supporting Evidence: PMID:18083836 This phosphorolytic processive enzyme uses inorganic phosphate and nucleotide diphosphate for degradation and polymerization activities, respectively. |
| GO:0000175 3'-5'-RNA exonuclease activity | IDA PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | ACCEPT | Summary: IDA: purified hSUV3-hPNPase complex degrades RNA in the 3'-to-5' direction, and PNPase alone degrades single-stranded substrates. Reason: Direct biochemical evidence; core activity. Supporting Evidence: PMID:19509288 The hSUV3-hPNPase complex prefers substrates containing a 3' overhang and degrades the RNA in a 3'-to-5' directionality. |
| GO:0000175 3'-5'-RNA exonuclease activity | TAS Reactome:R-HSA-9836585 | ACCEPT | Summary: Reactome reaction in which the SUPV3L1:PNPT1 degradosome degrades mitochondrial RNA to short oligoribonucleotides. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:19509288 The hSUV3-hPNPase complex prefers substrates containing a 3' overhang and degrades the RNA in a 3'-to-5' directionality. |
| GO:0000957 mitochondrial RNA catabolic process | IDA PMID:18501193 Human polynucleotide phosphorylase reduces oxidative RNA dam... | ACCEPT | Summary: IDA from a study showing PNPase limits oxidised (8-oxoG) RNA. The process (mitochondrial RNA catabolism) is a core PNPase role. Reason: PNPase degrades mitochondrial RNAs; the oxidised-RNA clearance data are consistent with this. Supporting Evidence: PMID:18501193 Our results suggest that hPNPase plays an important role in protecting cells and limiting damaged RNA under oxidative stress. |
| GO:0000957 mitochondrial RNA catabolic process | IDA PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | ACCEPT | Summary: IDA: the SUV3-PNPase degradosome efficiently degrades structured/double-stranded RNA substrates that neither component can degrade alone. Reason: Core process. Supporting Evidence: PMID:19509288 the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA and may be the long sought RNA-degrading complex in the mammalian mitochondria. |
| GO:0000957 mitochondrial RNA catabolic process | IDA PMID:29967381 Dedicated surveillance mechanism controls G-quadruplex formi... | ACCEPT | Summary: IDA: the degradosome, assisted by GRSF1, degrades G-quadruplex-forming mitochondrial non-coding RNAs. Reason: Core process. Supporting Evidence: PMID:29967381 a dedicated mechanism of degradation of G4-containing RNAs, which is based on cooperation between mitochondrial degradosome and quasi-RNA recognition motif (qRRM) protein GRSF1 |
| GO:0000957 mitochondrial RNA catabolic process | IDA PMID:39019044 RNA 5-methylcytosine marks mitochondrial double-stranded RNA... | ACCEPT | Summary: IDA: C1QBP recognises NSUN4-deposited m5C on light-strand mitochondrial RNAs and recruits PNPase to drive their turnover, limiting mt-dsRNA. Reason: Core process. Supporting Evidence: PMID:39019044 which recruits polyribonucleotide nucleotidyltransferase to facilitate RNA turnover |
| GO:0000957 mitochondrial RNA catabolic process | TAS Reactome:R-HSA-9836573 | ACCEPT | Summary: Reactome pathway Mitochondrial RNA degradation. Reason: Core process. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:0000958 mitochondrial mRNA catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA mitochondrial mRNA catabolic process. Reason: PNPase silencing increases mitochondrial transcript half-lives and causes accumulation of decay intermediates. Supporting Evidence: PMID:23221631 silencing of human polynucleotide phosphorylase (PNPase) causes accumulation of RNA decay intermediates and increases the half-life of mitochondrial transcripts |
| GO:0000958 mitochondrial mRNA catabolic process | IDA PMID:20691904 PNPASE regulates RNA import into mitochondria. | ACCEPT | Summary: IDA from the PNPase RNA-import study, which also reported impaired mitochondrial RNA processing upon PNPase reduction. Reason: Consistent with the established degradosome role in mt-mRNA turnover. Supporting Evidence: PMID:20691904 PNPASE reduction impaired mitochondrial RNA processing and polycistronic transcripts accumulated. |
| GO:0000958 mitochondrial mRNA catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation (ARBA, mouse ortholog) to mitochondrial mRNA catabolic process. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:23221631 silencing of human polynucleotide phosphorylase (PNPase) causes accumulation of RNA decay intermediates and increases the half-life of mitochondrial transcripts |
| GO:0000958 mitochondrial mRNA catabolic process | IMP PMID:22661577 LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promo... | ACCEPT | Summary: IMP: LRPPRC/SLIRP protects mitochondrial mRNAs against 3'-exonucleolytic decay mediated by PNPase and SUV3. Reason: Core process. Supporting Evidence: PMID:22661577 the LRPPRC/SLIRP complex suppressed 3' exonucleolytic mRNA degradation mediated by PNPase and SUV3 |
| GO:0000962 positive regulation of mitochondrial RNA catabolic process | IDA PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | MODIFY | Summary: IDA positive regulation of mitochondrial RNA catabolic process. PNPase is the catalytic exoribonuclease of the degradosome, not a regulator of the process. Reason: PNPase executes mitochondrial RNA degradation directly; the regulation term mis-describes its role. Replace with mitochondrial RNA catabolic process. Proposed replacements: mitochondrial RNA catabolic process Supporting Evidence: PMID:19509288 the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA |
| GO:0000964 mitochondrial RNA 5'-end processing | IMP PMID:18083837 Stable PNPase RNAi silencing: its effect on the processing a... | MARK AS OVER ANNOTATED | Summary: IMP mitochondrial RNA 5'-end processing from stable PNPase knockdown. The study reported effects on processing and polyadenylation but concluded PNPase acts most likely indirectly; 5'-end maturation of mitochondrial transcripts is carried out by mitochondrial RNase P. Reason: The authors themselves interpret the effect as indirect, and PNPase is a 3'-to-5' enzyme with no known 5'-processing activity. Supporting Evidence: PMID:18083837 is involved, most likely by indirect means, in the processing and polyadenylation of mtRNA |
| GO:0000965 mitochondrial RNA 3'-end processing | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA mitochondrial RNA 3'-end processing. PNPase trims 3' ends in bacteria and plastids; in human mitochondria PNPase depletion alters mRNA 3' ends and poly(A) tails, but the main role is decay. Reason: A plausible inherited 3'-trimming role with some support from knockdown data, but secondary to RNA degradation in human mitochondria. Supporting Evidence: PMID:18083837 Processing and polyadenylation of mt-mRNAs were significantly affected |
| GO:0000965 mitochondrial RNA 3'-end processing | IMP PMID:18083837 Stable PNPase RNAi silencing: its effect on the processing a... | KEEP AS NON CORE | Summary: IMP: stable PNPase knockdown significantly altered mt-mRNA processing and polyadenylation, differently for different transcripts. Reason: Supported phenotype, though the authors consider the involvement possibly indirect; non-core. Supporting Evidence: PMID:18083837 Processing and polyadenylation of mt-mRNAs were significantly affected |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro (KH/S1 domain) nucleic acid binding. Correct but generic. Reason: RNA binding is the more specific, separately annotated activity. Supporting Evidence: PMID:18083836 the degradation, polymerization, and RNA-binding properties of the human PNPase were analyzed |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | ACCEPT | Summary: High-throughput mRNA-bound proteome capture identified PNPT1. Reason: PNPase is an RNA-binding exoribonuclease (KH and S1 domains). Supporting Evidence: PMID:22681889 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. |
| GO:0003723 RNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based RNA binding. Reason: Consistent with direct RNA-binding studies of the purified enzyme. Supporting Evidence: PMID:18083836 the degradation, polymerization, and RNA-binding properties of the human PNPase were analyzed |
| GO:0004654 polyribonucleotide nucleotidyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA polyribonucleotide nucleotidyltransferase activity (EC 2.7.7.8). Reason: Defining activity of the PNPase family, confirmed for the human enzyme. Supporting Evidence: file:human/PNPT1/PNPT1-uniprot.txt EC=2.7.7.8 |
| GO:0004654 polyribonucleotide nucleotidyltransferase activity | IDA PMID:18083836 Analysis of the human polynucleotide phosphorylase (PNPase) ... | ACCEPT | Summary: IDA: purified human PNPase displays phosphorolytic degradation and NDP-dependent polymerisation activities. Reason: Direct biochemical evidence; core activity. Supporting Evidence: PMID:18083836 Phosphorolytic activity was displayed at lower optimum concentrations of inorganic phosphate. |
| GO:0004654 polyribonucleotide nucleotidyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (rat ortholog) polyribonucleotide nucleotidyltransferase activity. Reason: Consistent with experimental evidence. Supporting Evidence: file:human/PNPT1/PNPT1-uniprot.txt EC=2.7.7.8 |
| GO:0005515 protein binding | IPI PMID:16934922 The TCL1 oncoprotein binds the RNase PH domains of the PNPas... | REMOVE | Summary: PNPase identified in complex with the TCL1 oncoprotein, binding via the RNase PH domains without affecting RNA degradation. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative; the interaction does not alter PNPase activity and its physiological relevance is unclear. Supporting Evidence: PMID:16934922 The AKT interaction domain on TCL1 bound either RNase PH repeat domain of PNPase without influencing its RNA degrading activity |
| GO:0005515 protein binding | IPI PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | REMOVE | Summary: IPI with SUV3 (SUPV3L1), the partner helicase in the mitochondrial degradosome. Real and functionally central, but "protein binding" is uninformative; the relationship is captured by mitochondrial degradosome membership. Reason: protein binding (GO:0005515) is uninformative; the SUV3 interaction is captured by GO:0045025 mitochondrial degradosome. Supporting Evidence: PMID:19509288 the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex affinity-purification interaction with SUV3. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative; the SUV3 interaction is captured by degradosome membership. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:29967381 Dedicated surveillance mechanism controls G-quadruplex formi... | REMOVE | Summary: IPI with GRSF1, which cooperates with the degradosome in G-quadruplex RNA decay. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative; the functional relationship is captured by the mitochondrial RNA catabolic process annotation from the same study. Supporting Evidence: PMID:29967381 GRSF1 promotes G4 melting that facilitates degradosome-mediated decay |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary Y2H interaction with an ADARB1 isoform. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative and not linked to PNPase function. Supporting Evidence: PMID:32296183 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: BioPlex dual-network interaction with SUV3. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative; the SUV3 interaction is captured by degradosome membership. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:39251607 Systematic identification of post-transcriptional regulatory... | REMOVE | Summary: High-throughput post-transcriptional module screen interaction with SUV3. Reason: protein binding (GO:0005515) is uninformative; the SUV3 interaction is captured by degradosome membership. Supporting Evidence: PMID:39251607 Systematic identification of post-transcriptional regulatory modules. |
| GO:0005737 cytoplasm | IDA PMID:16055741 Defining the domains of human polynucleotide phosphorylase (... | KEEP AS NON CORE | Summary: IDA: fractionation of melanoma cells overexpressing hPNPase found it in mitochondria and cytoplasm. Endogenous PNPase is predominantly mitochondrial; the term is correct (mitochondria are part of the cytoplasm) but uninformative. Reason: Not wrong, but the functional location is the mitochondrion; an extramitochondrial cytosolic pool has been described mainly under overexpression. Supporting Evidence: PMID:16055741 Subcellular distribution confirmed hPNPase(OLD-35) to be localized both in mitochondria and the cytoplasm. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCell mapping to cytoplasm. Reason: Correct but uninformative relative to the mitochondrial annotations. Supporting Evidence: PMID:16055741 Subcellular distribution confirmed hPNPase(OLD-35) to be localized both in mitochondria and the cytoplasm. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-confidence human mitochondrial proteome. Reason: Consistent with targeted localisation studies. Supporting Evidence: PMID:12798676 Here, we demonstrate that the hPNPase is localized in mitochondria. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA is_active_in mitochondrion for the eukaryotic PNPase clade. Reason: Correct; metazoan PNPase acts in mitochondria. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localisation to mitochondria. Reason: Consistent with targeted studies. Supporting Evidence: PMID:12798676 Here, we demonstrate that the hPNPase is localized in mitochondria. |
| GO:0005739 mitochondrion | IDA PMID:16055741 Defining the domains of human polynucleotide phosphorylase (... | ACCEPT | Summary: IDA mitochondrial localisation from fractionation studies. Reason: Correct. Supporting Evidence: PMID:16055741 Subcellular distribution confirmed hPNPase(OLD-35) to be localized both in mitochondria and the cytoplasm. |
| GO:0005739 mitochondrion | IDA PMID:19864255 Human mitochondrial RNA turnover caught in flagranti: involv... | ACCEPT | Summary: IDA: PNPase co-purifies with the mitochondrial helicase hSuv3p. Reason: Correct. Supporting Evidence: PMID:19864255 hSuv3p co-purifies with PNPase |
| GO:0005739 mitochondrion | IDA PMID:20691904 PNPASE regulates RNA import into mitochondria. | ACCEPT | Summary: IDA mitochondrial localisation from the RNA import study. Reason: Correct. Supporting Evidence: PMID:20691904 we localized polynucleotide phosphorylase (PNPASE), a 3' --> 5' exoribonuclease and poly-A polymerase, in the mitochondrial intermembrane space |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of mitochondrion. Reason: Correct. Supporting Evidence: PMID:12798676 Here, we demonstrate that the hPNPase is localized in mitochondria. |
| GO:0005739 mitochondrion | NAS PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | ACCEPT | Summary: NAS mitochondrion from the degradosome reconstitution paper. Reason: Correct. Supporting Evidence: PMID:19509288 may be the long sought RNA-degrading complex in the mammalian mitochondria |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:16966381 Mammalian polynucleotide phosphorylase is an intermembrane s... | KEEP AS NON CORE | Summary: IDA: imported PNPase localised to the intermembrane space as a peripheral membrane protein in a multimeric complex. Later work confirmed a predominant IMS pool but also identified a minor matrix pool that forms the degradosome with SUV3 and carries out mitochondrial RNA decay. Reason: The IMS pool is supported by protease-protection experiments from more than one group, but the RNA-degrading function documented for PNPase is exerted by the matrix pool, so the IMS location is retained as non-core. Supporting Evidence: PMID:16966381 Once imported, PNPase localized to the intermembrane space (IMS) as a peripheral membrane protein in a multimeric complex. PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated (ARBA, mouse ortholog) intermembrane space annotation. Reason: See the IDA annotation; a real but non-core pool. Supporting Evidence: PMID:16966381 Once imported, PNPase localized to the intermembrane space (IMS) as a peripheral membrane protein in a multimeric complex. |
| GO:0005759 mitochondrial matrix | EXP PMID:12798676 Human polynucleotide phosphorylase, hPNPase, is localized in... | ACCEPT | Summary: EXP mitochondrial localisation of hPNPase (matrix assigned by curators). Reason: A matrix pool of PNPase is supported by protease-resistant mitoplast fractions and by its in vivo complex with matrix SUV3. Supporting Evidence: PMID:12798676 Here, we demonstrate that the hPNPase is localized in mitochondria. PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005759 mitochondrial matrix | EXP PMID:16055741 Defining the domains of human polynucleotide phosphorylase (... | ACCEPT | Summary: EXP mitochondrial matrix localisation from fractionation studies. Reason: Consistent with the functional matrix pool. Supporting Evidence: PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005759 mitochondrial matrix | IDA PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | ACCEPT | Summary: IDA is_active_in mitochondrial matrix, where the SUV3-PNPase degradosome acts. Reason: Core location of the degradosome activity. Supporting Evidence: PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005759 mitochondrial matrix | IDA PMID:39019044 RNA 5-methylcytosine marks mitochondrial double-stranded RNA... | ACCEPT | Summary: IDA matrix localisation from the NSUN4/C1QBP mt-dsRNA decay study. Reason: Core location. Supporting Evidence: PMID:39019044 which recruits polyribonucleotide nucleotidyltransferase to facilitate RNA turnover |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell mapping to mitochondrial matrix. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9836585 | ACCEPT | Summary: Reactome mitochondrial RNA degradation reactions placed in the matrix. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9836927 | ACCEPT | Summary: Reactome mitochondrial RNA degradation reactions placed in the matrix. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:23221631 a minor fraction of PNPase is localized in the mitochondrial matrix, where it can form a complex with the matrix-localized hSuv3 |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer of endoplasmic reticulum membrane from a rat PNPT1 annotation. No human evidence places PNPase in the ER membrane. Reason: PNPase is a mitochondrial protein imported via an N-terminal targeting sequence; an ER membrane location is unsupported for the human protein and inconsistent with its established localisation. Supporting Evidence: PMID:16966381 PNPase was efficiently imported into energized mitochondria with coupled processing of the N-terminal targeting sequence |
| GO:0005829 cytosol | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT IBA is_active_in cytosol, propagated from the bacterial PNPase ancestor (e.g. E. coli PNPase, a cytosolic degradosome component). Human PNPase is imported into mitochondria. Reason: The compartment of the bacterial ancestor does not transfer to the mitochondrially targeted metazoan enzyme; any cytosolic pool of human PNPase is minor and largely reported under overexpression. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000134193 SUPPORTS SOURCE BUT NOT TARGET Node carries the cytosolic location of bacterial PNPase (E. coli P05055), which does not apply to the mitochondrially imported human enzyme. Supporting Evidence: PMID:16966381 PNPase was efficiently imported into energized mitochondria with coupled processing of the N-terminal targeting sequence |
| GO:0005829 cytosol | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: Human Protein Atlas immunofluorescence assignment to cytosol. Reason: Antibody staining observation not supported by targeted studies, which find PNPase imported into mitochondria; not removed because it is experimental. Supporting Evidence: PMID:12798676 Here, we demonstrate that the hPNPase is localized in mitochondria. |
| GO:0005840 ribosome | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer of ribosome from a rat PNPT1 annotation. Reason: No evidence that human PNPase is a ribosome component; it is a mitochondrial exoribonuclease. The ortholog-transferred location is unsupported. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:0006396 RNA processing | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated RNA processing annotation; a real but secondary effect of PNPase. Reason: PNPase affects mitochondrial RNA processing; the core role is RNA catabolism. Supporting Evidence: PMID:20691904 PNPASE reduction impaired mitochondrial RNA processing and polycistronic transcripts accumulated. |
| GO:0006401 RNA catabolic process | IDA PMID:18083836 Analysis of the human polynucleotide phosphorylase (PNPase) ... | ACCEPT | Summary: IDA: purified human PNPase degrades RNA in vitro. Reason: Direct evidence; parent of the specific mitochondrial RNA catabolic process. Supporting Evidence: PMID:18083836 Phosphorolytic activity was displayed at lower optimum concentrations of inorganic phosphate. |
| GO:0006402 mRNA catabolic process | IDA PMID:12721301 Down-regulation of Myc as a potential target for growth arre... | KEEP AS NON CORE | Summary: IDA: overexpressed hPNPase(old-35) degraded c-myc mRNA in vitro and reduced c-myc expression in melanoma cells. This reflects activity of overexpressed enzyme on a cytoplasmic mRNA. Reason: GO:0006402 is the precise term for this claim: c-myc is a cytoplasmic transcript, so its degradation is not covered by GO:0000958 mitochondrial mRNA catabolic process, and no more specific term fits. Kept as non-core because the activity was shown with adenovirus-overexpressed enzyme; the physiological mRNA substrates are mitochondrial transcripts. Supporting Evidence: PMID:12721301 In vitro mRNA degradation assays revealed that hPNPaseOLD-35 degraded c-myc mRNA. |
| GO:0006402 mRNA catabolic process | IDA PMID:16055741 Defining the domains of human polynucleotide phosphorylase (... | KEEP AS NON CORE | Summary: IDA: either RNase PH domain of overexpressed hPNPase degraded c-myc mRNA. Reason: GO:0006402 is the precise term for c-myc mRNA degradation, a cytoplasmic transcript that GO:0000958 mitochondrial mRNA catabolic process does not cover. Kept as non-core because the evidence is overexpression of isolated RNase PH domains. Supporting Evidence: PMID:16055741 either one of the two RPH domains induced the morphological, biochemical, and gene expression changes associated with senescence, including degradation of c-myc mRNA |
| GO:0006402 mRNA catabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based mRNA catabolic process. Reason: Kept as non-core, consistent with the two c-myc IDA rows on the same term. mRNA catabolic process is the term that covers the reported cytoplasmic c-myc degradation, which GO:0000958 mitochondrial mRNA catabolic process (accepted separately, and the core process) does not entail; it is not a refinement candidate. Supporting Evidence: PMID:22661577 the LRPPRC/SLIRP complex suppressed 3' exonucleolytic mRNA degradation mediated by PNPase and SUV3 |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of mitochondrion organization from mouse Pnpt1. PNPase loss causes altered mitochondrial morphology and respiratory defects, downstream of RNA metabolism defects. Reason: Supported phenotypically (knockdown alters mitochondrial morphology and homeostasis) but an indirect consequence of PNPase's RNA functions. Supporting Evidence: PMID:16966381 decreased respiratory chain activity, and was correlated with altered mitochondrial morphology |
| GO:0007005 mitochondrion organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS mitochondrion organization from mouse Pnpt1. Reason: Indirect consequence of PNPase's RNA functions; non-core. Supporting Evidence: PMID:16966381 decreased respiratory chain activity, and was correlated with altered mitochondrial morphology |
| GO:0008266 poly(U) RNA binding | IDA PMID:18083836 Analysis of the human polynucleotide phosphorylase (PNPase) ... | KEEP AS NON CORE | Summary: IDA: purified human PNPase binding to ribohomopolymers, including poly(U). Reason: An in vitro substrate-binding property of a general RNA-binding exoribonuclease; not a sequence-specific physiological function. Supporting Evidence: PMID:18083836 the RNA-binding properties to ribohomopolymers varied significantly from those of its bacterial and organellar enzymes |
| GO:0034046 poly(G) binding | IDA PMID:18083836 Analysis of the human polynucleotide phosphorylase (PNPase) ... | KEEP AS NON CORE | Summary: IDA: purified human PNPase binding to ribohomopolymers, including poly(G). Reason: In vitro binding property; non-core. Supporting Evidence: PMID:18083836 the RNA-binding properties to ribohomopolymers varied significantly from those of its bacterial and organellar enzymes |
| GO:0034599 cellular response to oxidative stress | IDA PMID:18501193 Human polynucleotide phosphorylase reduces oxidative RNA dam... | KEEP AS NON CORE | Summary: IDA: PNPase overexpression reduces RNA oxidation and increases viability after H2O2, and knockdown has the opposite effect. Reason: Supported, plausibly through clearance of oxidised RNA by the exoribonuclease; non-core. Supporting Evidence: PMID:18501193 Overexpression of hPNPase reduces RNA oxidation and increases cell viability against H2O2 insult. |
| GO:0035198 miRNA binding | IDA PMID:20547861 Human polynucleotide phosphorylase selectively and preferent... | MARK AS OVER ANNOTATED | Summary: IDA: overexpressed hPNPase(old-35) immunoprecipitated with and degraded mature miR-221 in melanoma cells. Reason: Shown with adenoviral overexpression of a predominantly mitochondrial enzyme acting on a cytoplasmic miRNA; binding a miRNA substrate during degradation does not make miRNA binding a distinct physiological function of PNPase. Supporting Evidence: PMID:20547861 we confirm that mature miR-221 is the target of hPNPase(old-35) |
| GO:0035458 cellular response to interferon-beta | IDA PMID:16410805 Defining the mechanism by which IFN-beta dowregulates c-myc ... | KEEP AS NON CORE | Summary: IDA: PNPT1 is induced by IFN-beta, and its induction contributes to IFN-beta-mediated c-myc downregulation in melanoma cells. Reason: PNPT1 is an interferon-inducible gene and participates in an IFN-beta growth inhibitory response in melanoma cells; non-core. Supporting Evidence: PMID:16410805 we demonstrate that hPNPase(old-35) is a key molecule coupled with IFN-beta-mediated downregulation of c-myc mRNA |
| GO:0035927 RNA import into mitochondrion | IDA PMID:20691904 PNPASE regulates RNA import into mitochondria. | KEEP AS NON CORE | Summary: IDA: import of RNase P, 5S rRNA and MRP RNAs into the mitochondrial matrix depended on PNPase expression; reduced 5S rRNA and MRP RNA import was also reported in fibroblasts from a COXPD13 patient and rescued by wild-type PNPT1. The mechanism by which PNPase mediates RNA import remains unclear. Reason: Supported by more than one study, but the physiological extent of nuclear RNA import into mammalian mitochondria remains debated and PNPase's mechanistic role is undefined; its best-characterised role is mitochondrial RNA decay. Supporting Evidence: PMID:20691904 Augmented import of RNase P, 5S rRNA, and MRP RNAs depended on PNPASE expression PMID:23084291 we observed a significant decrease in 5S rRNA and MRP-related RNA import into mitochondria in fibroblasts of affected subject 1 |
| GO:0035928 rRNA import into mitochondrion | IDA PMID:20691904 PNPASE regulates RNA import into mitochondria. | KEEP AS NON CORE | Summary: IDA: PNPase-dependent import of 5S rRNA into mitochondria. Reason: See RNA import into mitochondrion; supported but non-core and mechanistically unresolved. Supporting Evidence: PMID:20691904 Augmented import of RNase P, 5S rRNA, and MRP RNAs depended on PNPASE expression PMID:23084291 overexpression of the wild-type PNPT1 cDNA in fibroblasts of subject 1 induced an increase in 5S rRNA import in mitochondria |
| GO:0042802 identical protein binding | IPI PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | KEEP AS NON CORE | Summary: IPI identical protein binding reflecting PNPase homotrimerisation. Reason: PNPase is a homotrimer, so self-association is real; it is a structural property rather than a function, and is captured by the homotrimerization process term. Supporting Evidence: file:human/PNPT1/PNPT1-uniprot.txt SUBUNIT: Homotrimer; in free form (PubMed:19509288). |
| GO:0043457 regulation of cellular respiration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of regulation of cellular respiration from mouse Pnpt1. Reason: Respiratory defects after PNPase loss are a downstream consequence of disturbed mitochondrial RNA metabolism and mtDNA loss, not a regulatory function. Supporting Evidence: PMID:30024931 PNPase knockout results in mtDNA loss and an altered metabolic gene expression |
| GO:0043457 regulation of cellular respiration | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS regulation of cellular respiration from mouse Pnpt1. Reason: Indirect consequence of RNA-metabolism defects; see IEA. Supporting Evidence: PMID:16966381 decreased respiratory chain activity, and was correlated with altered mitochondrial morphology |
| GO:0045025 mitochondrial degradosome | IDA PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | ACCEPT | Summary: IDA: purified SUV3 dimer and PNPase trimer form a 330-kDa heteropentameric degradosome that degrades dsRNA in an ATP-dependent manner. Reason: Core complex membership. Supporting Evidence: PMID:19509288 the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA |
| GO:0045025 mitochondrial degradosome | IDA PMID:29967381 Dedicated surveillance mechanism controls G-quadruplex formi... | ACCEPT | Summary: IDA degradosome membership from the GRSF1/G4 RNA decay study. Reason: Core complex membership. Supporting Evidence: PMID:29967381 In vitro reconstitution experiments show that GRSF1 promotes G4 melting that facilitates degradosome-mediated decay. |
| GO:0045025 mitochondrial degradosome | IPI PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | ACCEPT | Summary: IPI degradosome membership (PNPase-SUV3 interaction). Reason: Core complex membership. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:0051260 protein homooligomerization | IDA PMID:20691904 PNPASE regulates RNA import into mitochondria. | KEEP AS NON CORE | Summary: IDA protein homooligomerization (PNPase trimer formation). Reason: Trimerisation is required for activity and is disrupted by disease variants, but it is a structural property; non-core. Supporting Evidence: PMID:23084291 confirming that the substitution encoded by c.1160A>G disrupts the trimerization of the protein |
| GO:0051591 response to cAMP | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of response to cAMP from rat Pnpt1 (expression response). Reason: An expression-change observation in rat transferred to human; it does not describe a function of PNPase. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:0060416 response to growth hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of response to growth hormone from rat Pnpt1. Reason: An expression-change observation in rat transferred to human; not a function of PNPase. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:0061014 positive regulation of mRNA catabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of positive regulation of mRNA catabolic process from rat. PNPase degrades mRNA directly rather than regulating its catabolism. Reason: PNPase is the nuclease; the direct process is mRNA catabolism (mitochondrial mRNA catabolic process in its physiological setting). Proposed replacements: mitochondrial mRNA catabolic process Supporting Evidence: PMID:22661577 the LRPPRC/SLIRP complex suppressed 3' exonucleolytic mRNA degradation mediated by PNPase and SUV3 |
| GO:0061014 positive regulation of mRNA catabolic process | IMP PMID:16410805 Defining the mechanism by which IFN-beta dowregulates c-myc ... | MODIFY | Summary: IMP: knockdown of IFN-beta-induced PNPase prevented c-myc mRNA downregulation. PNPase degrades c-myc mRNA directly, so its role is catalytic rather than regulatory. Reason: The study's own model is direct degradation of c-myc mRNA by PNPase; the correct framing is mRNA catabolic process, not its positive regulation. Proposed replacements: mRNA catabolic process Supporting Evidence: PMID:16410805 induces G1 cell cycle arrest and eventually apoptosis by specifically degrading c-myc mRNA |
| GO:0070207 protein homotrimerization | IDA PMID:19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase fo... | KEEP AS NON CORE | Summary: IDA protein homotrimerization; PNPase exists as a homotrimer in free form. Reason: Structural property required for activity; non-core. Supporting Evidence: file:human/PNPT1/PNPT1-uniprot.txt SUBUNIT: Homotrimer; in free form (PubMed:19509288). |
| GO:0070207 protein homotrimerization | IDA PMID:20691904 PNPASE regulates RNA import into mitochondria. | KEEP AS NON CORE | Summary: IDA protein homotrimerization from the RNA import study. Reason: Structural property; non-core. Supporting Evidence: PMID:23084290 the identified mutation results in a hypofunctional protein leading to disturbed PNPase trimerization and impaired mitochondrial RNA import |
| GO:0071042 nuclear polyadenylation-dependent mRNA catabolic process | IDA PMID:16934922 The TCL1 oncoprotein binds the RNase PH domains of the PNPas... | MODIFY | Summary: IDA nuclear polyadenylation-dependent mRNA catabolic process from the TCL1 study, which measured PNPase RNA-degrading activity in vitro. The term describes nuclear exosome-mediated decay, which PNPase (a mitochondrial enzyme) does not perform. Reason: The evidence supports RNA degradation by PNPase in vitro, not a nuclear, polyadenylation-dependent pathway. Replace with the general RNA catabolic process. Proposed replacements: RNA catabolic process Supporting Evidence: PMID:16934922 bound either RNase PH repeat domain of PNPase without influencing its RNA degrading activity |
| GO:0097222 mitochondrial mRNA polyadenylation | IMP PMID:18083837 Stable PNPase RNAi silencing: its effect on the processing a... | MARK AS OVER ANNOTATED | Summary: IMP mitochondrial mRNA polyadenylation from stable PNPase knockdown, which altered poly(A) tails in a transcript-specific manner. The mitochondrial poly(A) polymerase is MTPAP; the authors concluded PNPase acts most likely indirectly. Reason: PNPase knockdown changes poly(A) tail length, but the authors attribute this to indirect effects and identify other polymerases as responsible for adenylation. Supporting Evidence: PMID:18083837 is involved, most likely by indirect means, in the processing and polyadenylation of mtRNA |
| GO:0097421 liver regeneration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of liver regeneration from rat Pnpt1 (expression-based). Reason: An organismal expression observation in rat; it does not describe a function of PNPase. Supporting Evidence: PMID:23221631 PNPase and hSuv3 helicase (Suv3, hSuv3p and SUPV3L1) form the RNA-degrading complex in vivo in human mitochondria |
| GO:1905354 exoribonuclease complex | IEA GO_REF:0000117 | MODIFY | Summary: ARBA exoribonuclease complex. Correct in essence (the PNPase trimer and the degradosome are exoribonuclease complexes) but the specific complex is the mitochondrial degradosome. Reason: Replace with the specific complex term. Proposed replacements: mitochondrial degradosome Supporting Evidence: PMID:19509288 the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA |
| GO:2000627 positive regulation of miRNA catabolic process | IDA PMID:20547861 Human polynucleotide phosphorylase selectively and preferent... | MARK AS OVER ANNOTATED | Summary: IDA positive regulation of miRNA catabolic process: overexpressed PNPase degraded miR-221 in melanoma cells. PNPase acted as the nuclease rather than a regulator, and the result depends on overexpression. Reason: Overexpression-based evidence for cytoplasmic miRNA degradation by a predominantly mitochondrial enzyme; the regulatory framing also misdescribes a direct catalytic role. Supporting Evidence: PMID:20547861 we confirm that mature miR-221 is the target of hPNPase(old-35) |
| GO:2000772 regulation of cellular senescence | IDA PMID:16055741 Defining the domains of human polynucleotide phosphorylase (... | MARK AS OVER ANNOTATED | Summary: IDA regulation of cellular senescence: overexpression of hPNPase (or either RNase PH domain) induced senescence-associated changes in melanoma cells and melanocytes. Reason: Induced by forced overexpression; PNPase is upregulated in senescent cells, but a physiological role in regulating senescence has not been shown with loss of function. Supporting Evidence: PMID:16055741 either one of the two RPH domains induced the morphological, biochemical, and gene expression changes associated with senescence |
Loading supporting content…
Download this section (compressed HTML)Q: GO:0000175 3'-5'-RNA exonuclease activity, accepted here as the core molecular function, is_a GO:0016896 (hydrolysis yielding 5'-phosphomonoesters), whereas PNPase is phosphorolytic. The E. coli and P. putida pnp reviews modify GO:0000175 to GO:0004654, and the PTHR11252 family review leaves GO:0000175 UNRESOLVED pending a GO decision. Should GO make GO:0000175 mechanism-neutral, or should PNPT1 be annotated only to GO:0004654?
Q: How do the intermembrane-space and matrix pools of PNPase partition, and does the IMS pool have a function (for example in RNA import or in mt-dsRNA release) distinct from the matrix degradosome?
Q: What is the mechanism of the PNPase-dependent escape of mitochondrial double-stranded RNA into the cytosol, given that PNPase loss both increases mt-dsRNA and is required for its release?
Q: Is PNPase-dependent import of nuclear RNAs (5S rRNA, RNase P and MRP RNAs) into mammalian mitochondria physiologically significant, and does its loss contribute to the hearing loss and encephalomyopathy phenotypes independently of RNA decay defects?
Experiment: Express IMS-restricted and matrix-restricted PNPase variants in PNPT1-null cells and measure mt-dsRNA levels, cytosolic mt-dsRNA release, interferon-stimulated gene expression and mitochondrial translation.
Experiment: Compare the catalytic activity, trimer stability and SUV3 binding of recombinant COXPD13 and hearing-loss PNPT1 variants to relate residual degradosome activity to phenotype severity.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)