ARRDC5 is a testis-enriched alpha-arrestin (arrestin domain-containing) protein required for male fertility. Arrdc5-null mice are male-sterile, with defective spermiogenesis that yields few, immotile and malformed sperm. ARRDC5 influences SEC22A-mediated trafficking of the head-tail coupling proteins NDC1 and SUN5, binds TEX38 to drive biogenesis and migration of the sperm cytoplasmic droplet, and forms a complex with TEX38, CLGN and PDILT needed for ADAM3 maturation and sperm migration to the oviduct.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cytoplasm (IBA, alpha-arrestin node). The family is cytoplasmic. ARRDC5 itself is studied only in developing sperm, where it acts in protein trafficking and cytoplasmic-droplet formation. In mouse, ARRDC5 is reported to be highly enriched in the sperm cytoplasmic droplet, a remnant of spermatid cytoplasm. Kept as non-core. Reason: [PMID:41420860 "Interestingly, ARRDC5 protein was reported to be highly enriched in the CDs of sperm isolated from the epididymis of wild-type mice."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000127176 SUPPORTS TRANSFER Alpha-arrestin node seeded by fungal, fly, Dictyostelium, mouse and human arrestin-domain proteins; ARRDC5 is not among the seeds. Supporting Evidence: PMID:41420860 Interestingly, ARRDC5 protein was reported to be highly enriched in the CDs of sperm isolated from the epididymis of wild-type mice. |
| GO:0005768 endosome | IBA GO_REF:0000033 | UNDECIDED | Summary: Endosome (IBA). The node's only seed is ARRDC3, a somatic alpha-arrestin at the plasma membrane and endosomes. ARRDC5 is testis-restricted and acts in spermatid protein trafficking and cytoplasmic-droplet biogenesis. ARRDC5 is the divergent family member: it lacks the PY motifs, has a divergent sequence, and is testis-restricted, and it was set apart from the alpha-arrestins whose plasma-membrane and vesicle localization was characterized. No ARRDC5 localization to this compartment has been reported. The transfer is neither supported nor contradicted by ARRDC5 data. Reason: The only seed (ARRDC3) is a somatic PY-motif alpha-arrestin; ARRDC5 differs on each count. [PMID:23236378 "Five of six mammalian aArrs, but not ARRDC5 (which has overall divergent protein sequence, no PY motifs, and testis-predominant expression), are broadly expressed, suggesting they may be promiscuous like bArrs."] [PMID:37069147 "Multispecies testicular tissue transcriptome profiling indicates that expression of Arrdc5 is testis enriched, if not specific, in mice, pigs, cattle, and humans."] Propagation Review Root cause: UNRESOLVED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN008513893 SUPPORTS SOURCE BUT NOT TARGET ARRDC3 node, seeded only by human ARRDC3 (UniProtKB:Q96B67) from somatic cells. ARRDC5 has a testis-specific role, and no localization data exist for it. Supporting Evidence: PMID:23236378 Five of six mammalian aArrs, but not ARRDC5 (which has overall divergent protein sequence, no PY motifs, and testis-predominant expression), are broadly expressed, suggesting they may be promiscuous like bArrs. PMID:37069147 Multispecies testicular tissue transcriptome profiling indicates that expression of Arrdc5 is testis enriched, if not specific, in mice, pigs, cattle, and humans. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | UNDECIDED | Summary: Plasma membrane (IBA). The node's only seed is ARRDC3, a somatic alpha-arrestin at the plasma membrane and endosomes. ARRDC5 is testis-restricted and acts in spermatid protein trafficking and cytoplasmic-droplet biogenesis. ARRDC5 is the divergent family member: it lacks the PY motifs, has a divergent sequence, and is testis-restricted, and it was set apart from the alpha-arrestins whose plasma-membrane and vesicle localization was characterized. No ARRDC5 localization to this compartment has been reported. The transfer is neither supported nor contradicted by ARRDC5 data. Reason: The only seed (ARRDC3) is a somatic PY-motif alpha-arrestin; ARRDC5 differs on each count. [PMID:23236378 "Five of six mammalian aArrs, but not ARRDC5 (which has overall divergent protein sequence, no PY motifs, and testis-predominant expression), are broadly expressed, suggesting they may be promiscuous like bArrs."] [PMID:37069147 "Multispecies testicular tissue transcriptome profiling indicates that expression of Arrdc5 is testis enriched, if not specific, in mice, pigs, cattle, and humans."] Propagation Review Root cause: UNRESOLVED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN008513893 SUPPORTS SOURCE BUT NOT TARGET ARRDC3 node, seeded only by human ARRDC3 (UniProtKB:Q96B67) from somatic cells. ARRDC5 has a testis-specific role, and no localization data exist for it. Supporting Evidence: PMID:23236378 Five of six mammalian aArrs, but not ARRDC5 (which has overall divergent protein sequence, no PY motifs, and testis-predominant expression), are broadly expressed, suggesting they may be promiscuous like bArrs. PMID:37069147 Multispecies testicular tissue transcriptome profiling indicates that expression of Arrdc5 is testis enriched, if not specific, in mice, pigs, cattle, and humans. |
| GO:0007283 spermatogenesis | ISS GO_REF:0000024 | MODIFY | Summary: Spermatogenesis (ISS, from mouse Arrdc5). Arrdc5-null mice are male-sterile, with few immotile, malformed sperm. The testicular defect is in spermiogenesis, the spermatid-to-sperm transformation, so the term is modified to spermatid development. Later roles after the testis (cytoplasmic-droplet migration during epididymal maturation, ADAM3 maturation for sperm migration to the oviduct) are not covered by this term and are recorded as a question. Reason: [PMID:37069147 "Knockout of Arrdc5 in mice leads to male specific sterility due to production of low numbers of sperm that are immotile and malformed."] [PMID:37069147 "Spermiogenesis, the final phase of spermatogenesis when round spermatids transform to spermatozoa, is defective in testes of Arrdc5 deficient mice."] Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q497K5 SUPPORTS TRANSFER Mouse Arrdc5 (UniProtKB:Q497K5); donor IMP (PMID:37069147, PMID:37997706). The phenotype is specifically in spermiogenesis. Proposed replacements: spermatid development Supporting Evidence: PMID:37069147 Knockout of Arrdc5 in mice leads to male specific sterility due to production of low numbers of sperm that are immotile and malformed. PMID:37069147 Spermiogenesis, the final phase of spermatogenesis when round spermatids transform to spermatozoa, is defective in testes of Arrdc5 deficient mice. |
| GO:0016020 membrane | IEA GO_REF:0000044 | UNDECIDED | Summary: Membrane (IEA, UniProt subcellular location mapping). The source is A6NEK1's own UniProt location line, which is itself by similarity to mouse Arrdc5. That mouse membrane call (UniProt IDA, PMID:37069147; EXP, PMID:37997706) cannot be checked in the cached texts: the full text of PMID:37069147 has no ARRDC5 membrane statement, and PMID:37997706 is abstract-only. Deferring; undecided. Reason: [file:human/ARRDC5/ARRDC5-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q497K5}."] The mouse donor evidence is not visible in the cached papers. Supporting Evidence: file:human/ARRDC5/ARRDC5-uniprot.txt CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q497K5}. |
| GO:0016020 membrane | ISS GO_REF:0000024 | UNDECIDED | Summary: Membrane (ISS, from mouse Arrdc5). The donor rows are UniProt-curated mouse IDA (PMID:37069147) and EXP (PMID:37997706). The cached full text of PMID:37069147 contains no ARRDC5 membrane-localization statement, and PMID:37997706 is abstract-only, so the donor evidence cannot be checked here. A trafficking role near membranes is plausible but not a localization. Undecided, deferring to the donor curation. Reason: The cached mouse papers do not show ARRDC5 membrane localization; the SEC22A trafficking sentence describes an effect on other proteins, not where ARRDC5 sits. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q497K5 SUPPORTS TRANSFER Mouse Arrdc5 (UniProtKB:Q497K5); UniProt donor IDA/EXP membrane rows (PMID:37069147, PMID:37997706). Orthology is clear, but the donor localization is not visible in the cached papers. |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Molecular adaptor activity (IBA, alpha-arrestin node). ARRDC5 acts as a scaffold in sperm maturation: it binds TEX38 and forms a complex with CLGN and PDILT, and it controls trafficking of the head-tail coupling proteins NDC1 and SUN5. What is shown is complex membership and a trafficking effect, not a demonstrated bridging step. Because ARRDC5 lacks PY motifs, the family's HECT-ligase recruitment mechanism does not apply. A protein scaffold remains the best fit; modified to protein-macromolecule adaptor activity. Reason: [PMID:41420860 "Here, we demonstrate that two proteins with testis-specific expression, arrestin domain-containing 5 (ARRDC5) and testis expressed 38 (TEX38), physically interact, are required for normal sperm maturation, and play a critical role in CD formation and function."] [PMID:40783453 "Immunoprecipitation-mass spectrometry identified TEX38 and ARRDC5 interact with CLGN and PDILT."] [PMID:37997706 "We further found that ARRDC5 might affect the vesicle-trafficking protein SEC22A-mediated transport and localization of NDC1, SUN5 and other head-tail coupling apparatus-related proteins that are responsible for initiating the attachment of the sperm head and tail."] [PMID:23236378 "With the exception of ARRDC5, all mammalian aArrs have a pair of PY motifs."] Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000127176 SUPPORTS TRANSFER Alpha-arrestin node; ARRDC5 is not among the seeds. A scaffold role transfers, but the seeds' PY-motif ligase recruitment does not, as ARRDC5 lacks PY motifs. ARRDC5 has its own complex-membership evidence in sperm. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:41420860 Here, we demonstrate that two proteins with testis-specific expression, arrestin domain-containing 5 (ARRDC5) and testis expressed 38 (TEX38), physically interact, are required for normal sperm maturation, and play a critical role in CD formation and function. PMID:40783453 Immunoprecipitation-mass spectrometry identified TEX38 and ARRDC5 interact with CLGN and PDILT. PMID:37997706 We further found that ARRDC5 might affect the vesicle-trafficking protein SEC22A-mediated transport and localization of NDC1, SUN5 and other head-tail coupling apparatus-related proteins that are responsible for initiating the attachment of the sperm head and tail. PMID:23236378 With the exception of ARRDC5, all mammalian aArrs have a pair of PY motifs. |
Loading supporting content…
Download this section (compressed HTML)Q: Lacking PY motifs, how does ARRDC5 sort cargo, and does its V-type ATPase interaction underlie cytoplasmic-droplet or acrosome function?
Q: Which process terms should capture ARRDC5's post-testicular roles in cytoplasmic-droplet migration and ADAM3-dependent sperm migration to the oviduct?
Experiment: Localize endogenous ARRDC5 in human spermatids, and test whether ARRDC5 variants occur in men with asthenoteratozoospermia.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)