SUN5 (SPAG4L, TSARG4) is a testis-enriched SUN-domain protein of the nuclear envelope, a 379-residue single-pass protein with a nucleoplasmic N-terminus, a luminal coiled coil and a C-terminal SUN domain. In spermatids it is glycosylated during transit through the Golgi, reaches the nuclear envelope and then concentrates at the posterior pole of the elongating nucleus, the implantation fossa, where the sperm head-tail coupling apparatus (connecting piece, basal plate and proximal centriole) docks; in mature sperm it marks the neck. There SUN5 forms a LINC complex with the KASH protein Nesprin-3 (SYNE3), which it is required to position at the posterior nuclear membrane, and it binds lamin B1 on the nucleoplasmic side, anchoring the coupling apparatus and flagellum to the nucleus. Loss of SUN5 in mice leaves meiosis, acrosome formation and nuclear condensation intact but the coupling apparatus detaches from the nucleus during spermatid elongation, producing headless (acephalic) spermatozoa and male infertility. Biallelic SUN5 variants are the most frequent cause of human acephalic spermatozoa syndrome (spermatogenic failure 16), which can be bypassed by intracytoplasmic injection of sperm heads.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid interaction with SPAG4 (SUN4). Reason: GO:0005515 protein binding is uninformative; removal does not imply the SUN5-SUN4 interaction is false. A single binary-screen hit between two testis SUN proteins may reflect SUN-domain/coiled-coil hetero-association but has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:38870534 SUN5 interacts with nuclear membrane LaminB1 and cytoskeleta... | MODIFY | Summary: SUN5 interacts with lamin B1 (IP-MS in mouse testis, confirmed by follow-up assays); proposed to connect SUN5 to the nucleus at the head-tail junction. Reason: Generic protein binding is uninformative. The partner is lamin B1, a B-type lamin, and the paper interprets the interaction as SUN5 linking to the nuclear lamina, which GO:0005521 lamin binding captures (as for SUN1/SUN2). Cached text is abstract-only. Proposed replacements: lamin binding Supporting Evidence: PMID:38870534 SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12 |
| GO:0005515 protein binding | IPI PMID:38870534 SUN5 interacts with nuclear membrane LaminB1 and cytoskeleta... | REMOVE | Summary: SUN5 interacts with SEPTIN2 (IP-MS from mouse testis and follow-up); proposed LaminB1/SUN5/Septin12 bridge to the proximal centriole. Reason: GO:0005515 protein binding is uninformative and GO has no septin-binding MF; removal does not imply the interaction is false. The functional consequence (anchoring the coupling apparatus to the nuclear envelope) is captured by protein-membrane adaptor activity and the spermatid development / head-tail coupling apparatus terms. Note that septins are cytoplasmic whereas the SUN domain is luminal, so the topology of a direct SUN5-septin contact is unresolved (cached text is abstract-only). Supporting Evidence: PMID:38870534 LaminB1 and cytoskeletal GTPases Septin12 and Septin2 were identified as potential partners for interacting with SUN5 by immunoprecipitation-mass spectrometry in mouse testis |
| GO:0005515 protein binding | IPI PMID:38870534 SUN5 interacts with nuclear membrane LaminB1 and cytoskeleta... | REMOVE | Summary: SUN5 interacts with SEPTIN12 (IP-MS from mouse testis and follow-up); proposed LaminB1/SUN5/Septin12 bridge to the proximal centriole. Reason: GO:0005515 protein binding is uninformative and GO has no septin-binding MF; removal does not imply the interaction is false. The functional consequence (anchoring the coupling apparatus to the nuclear envelope) is captured by protein-membrane adaptor activity and the spermatid development / head-tail coupling apparatus terms. Note that septins are cytoplasmic whereas the SUN domain is luminal, so the topology of a direct SUN5-septin contact is unresolved (cached text is abstract-only). Supporting Evidence: PMID:38870534 LaminB1 and cytoskeletal GTPases Septin12 and Septin2 were identified as potential partners for interacting with SUN5 by immunoprecipitation-mass spectrometry in mouse testis |
| GO:0005635 nuclear envelope | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear envelope (IBA from the SUN-domain family). Reason: SUN5 is a SUN-domain nuclear envelope protein in round spermatids that later concentrates at the posterior nuclear envelope/implantation fossa; the PAINT node placement across SUN proteins is sound here. Supporting Evidence: PMID:25775128 In round spermatids, it progresses to the Golgi and the NE before to be located to the tail/head junction in epididymal sperm. PMID:28945193 In mature spermatozoa, SUN5 was localized to the coupling apparatus of the sperm head and tail in the implantation fossa |
| GO:0005637 nuclear inner membrane | IDA PMID:27640305 Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic... | ACCEPT | Summary: Nuclear inner membrane. Reason: SUN5 is a single-pass SUN-domain protein with nucleoplasmic N-terminus and luminal SUN domain, the canonical INM topology. The cited paper states INM location (largely by reference to prior work) and shows SUN5 at the head-tail junction; consistent with the family and with SUN5-Nesprin3 LINC formation. Supporting Evidence: PMID:27640305 SUN5 is a 379-amino-acid transmembrane protein located in the inner nuclear membrane (INM) file:human/SUN5/SUN5-uniprot.txt SUBCELLULAR LOCATION: Nucleus inner membrane |
| GO:0005637 nuclear inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear inner membrane. Reason: SUN5 is a single-pass SUN-domain protein with nucleoplasmic N-terminus and luminal SUN domain, the canonical INM topology. The cited paper states INM location (largely by reference to prior work) and shows SUN5 at the head-tail junction; consistent with the family and with SUN5-Nesprin3 LINC formation. Supporting Evidence: PMID:27640305 SUN5 is a 379-amino-acid transmembrane protein located in the inner nuclear membrane (INM) file:human/SUN5/SUN5-uniprot.txt SUBCELLULAR LOCATION: Nucleus inner membrane |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi apparatus (transit compartment during spermiogenesis). Reason: Mouse Sun5 transits through the Golgi in round spermatids, where it is glycosylated, before reaching the nuclear envelope; a genuine but transient biosynthetic location, not where SUN5 acts. Supporting Evidence: PMID:25775128 Finally, we show that Sun5 transits through the Golgi apparatus, leading to post-translational modifications PMID:25775128 In round spermatids, it progresses to the Golgi and the NE before to be located to the tail/head junction in epididymal sperm. |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi apparatus (transit compartment during spermiogenesis). Reason: Mouse Sun5 transits through the Golgi in round spermatids, where it is glycosylated, before reaching the nuclear envelope; a genuine but transient biosynthetic location, not where SUN5 acts. Supporting Evidence: PMID:25775128 Finally, we show that Sun5 transits through the Golgi apparatus, leading to post-translational modifications PMID:25775128 In round spermatids, it progresses to the Golgi and the NE before to be located to the tail/head junction in epididymal sperm. |
| GO:0007283 spermatogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: Spermatogenesis (ARBA). Reason: Correct but general; SUN5 acts in spermiogenesis (spermatid development) and its loss causes acephalic spermatozoa. Supporting Evidence: PMID:28945193 We found that knockout of Sun5 has no effects on mouse meiosis, acrosome biogenesis or sperm nuclear remodeling, but it specifically destroyed the integrity of the spermatozoa, ultimately resulting in acephalic spermatozoa. PMID:27640305 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm |
| GO:0007283 spermatogenesis | IEP PMID:12621555 [Cloning of cDNA of TSARG4, a human spermatogenesis related ... | ACCEPT | Summary: Spermatogenesis, from expression of TSARG4 (SUN5) cDNA. Reason: The expression evidence itself is weak (the cloning paper reports broad adult-tissue mRNA expression), but SUN5 involvement in spermatogenesis is firmly established by knockout and human genetics; the more specific process is spermatid development. Supporting Evidence: PMID:12621555 The human TSARG4 mRNA is expressed in a wide range of adult tissues, including testis PMID:28945193 We found that knockout of Sun5 has no effects on mouse meiosis, acrosome biogenesis or sperm nuclear remodeling, but it specifically destroyed the integrity of the spermatozoa, ultimately resulting in acephalic spermatozoa. |
| GO:0007286 spermatid development | IMP PMID:38870534 SUN5 interacts with nuclear membrane LaminB1 and cytoskeleta... | ACCEPT | Summary: Spermatid development: Sun5 knockout causes acephalic spermatozoa because the head-tail coupling apparatus detaches from the nucleus during spermatid elongation. Reason: Core process. SUN5 does part of the work by anchoring the coupling apparatus to the posterior nuclear envelope; mouse knockouts from several groups and human biallelic variants all give acephalic spermatozoa, while meiosis is unaffected. Supporting Evidence: PMID:38870534 we generated Sun5 knockout mice, which presented the phenotype of ASS PMID:28945193 without functional SUN5, the coupling apparatus together with the basal plate disassociated from the implantation fossa during the elongation of the spermatids PMID:28945193 We found that knockout of Sun5 has no effects on mouse meiosis, acrosome biogenesis or sperm nuclear remodeling, but it specifically destroyed the integrity of the spermatozoa, ultimately resulting in acephalic spermatozoa. PMID:34268309 Our findings suggested that Sun5 is essential for the localization of Nesprin3 at the posterior nuclear membrane |
| GO:0007286 spermatid development | ISS GO_REF:0000024 | ACCEPT | Summary: Spermatid development: Sun5 knockout causes acephalic spermatozoa because the head-tail coupling apparatus detaches from the nucleus during spermatid elongation. Reason: Core process. SUN5 does part of the work by anchoring the coupling apparatus to the posterior nuclear envelope; mouse knockouts from several groups and human biallelic variants all give acephalic spermatozoa, while meiosis is unaffected. Supporting Evidence: PMID:38870534 we generated Sun5 knockout mice, which presented the phenotype of ASS PMID:28945193 without functional SUN5, the coupling apparatus together with the basal plate disassociated from the implantation fossa during the elongation of the spermatids PMID:28945193 We found that knockout of Sun5 has no effects on mouse meiosis, acrosome biogenesis or sperm nuclear remodeling, but it specifically destroyed the integrity of the spermatozoa, ultimately resulting in acephalic spermatozoa. PMID:34268309 Our findings suggested that Sun5 is essential for the localization of Nesprin3 at the posterior nuclear membrane |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IBA GO_REF:0000033 | MODIFY | Summary: Meiotic nuclear membrane microtubule tethering complex (IBA). Reason: SUN5 does form a LINC complex, but with Nesprin3 in post-meiotic spermatids at the head-tail junction; Sun5 knockout has no effect on meiosis. The meiotic-specific child term is therefore wrong for SUN5, whereas the parent GO:0106094 nuclear membrane microtubule tethering complex (the general LINC complex term used in the SUN1/SUN2/SYNE reviews) is supported. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000308197 SUPPORTS SOURCE BUT NOT TARGET SUN node carrying the meiotic LINC IBD, grounded in SUN1/SUN2 (mammal), Sad1 (fission yeast) and SUN-1 (worm) meiotic telomere/pairing-centre roles. SUN5 falls inside the clade, but its function has diverged to post-meiotic sperm head-tail anchoring with Nesprin3; LINC membership transfers, the meiotic context does not. UniProtKB:O94901 · SUN1 SUPPORTS SOURCE BUT NOT TARGET Genuine meiotic SUN1:KASH5 complex member; supports the node but not SUN5 meiotic function. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:28945193 We found that knockout of Sun5 has no effects on mouse meiosis, acrosome biogenesis or sperm nuclear remodeling, but it specifically destroyed the integrity of the spermatozoa, ultimately resulting in acephalic spermatozoa. PMID:34268309 Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex PMID:33848337 The co-immunoprecipitation analysis indicated that SUN5 and ODF1, SUN5 and Nesprin3, and ODF1 and Nesprin3 interacted with each other in transfected HEK293T cells. |
| GO:0043495 protein-membrane adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Protein-membrane adaptor activity (IBA from the SUN-domain family). Reason: Consistent with SUN5 function: a nuclear envelope membrane protein that binds Nesprin3 (luminally) and lamin B1 (nucleoplasmically) to hold the head-tail coupling apparatus at the posterior nuclear membrane. Same MF accepted for SUN1/SUN2 family members. Supporting Evidence: PMID:34268309 Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex PMID:34268309 Our findings suggested that Sun5 is essential for the localization of Nesprin3 at the posterior nuclear membrane PMID:38870534 SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12 |
| GO:0120212 sperm head-tail coupling apparatus | IDA PMID:27640305 Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic... | ACCEPT | Summary: Sperm head-tail coupling apparatus: SUN5 localizes to the human sperm head-tail junction, altered by patient variants. Reason: Core location, confirmed in mouse at the implantation fossa/coupling apparatus. Supporting Evidence: PMID:27640305 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm PMID:28945193 In mature spermatozoa, SUN5 was localized to the coupling apparatus of the sperm head and tail in the implantation fossa |
| GO:0120212 sperm head-tail coupling apparatus | ISS GO_REF:0000024 | ACCEPT | Summary: Sperm head-tail coupling apparatus (ISS from mouse). Reason: Core location. Supporting Evidence: PMID:28945193 In mature spermatozoa, SUN5 was localized to the coupling apparatus of the sperm head and tail in the implantation fossa |
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Download this section (compressed HTML)Q: What is the topology of SUN5 at the implantation fossa: how can a luminal SUN domain contact cytoplasmic Septin12/ODF1, i.e. are these interactions indirect via Nesprin-3, or does the specialized posterior nuclear envelope alter SUN5 orientation?
Suggested experts: sperm cell biologists, nuclear envelope biologists
Q: Is Nesprin-3 the only KASH partner of SUN5 in vivo, and does the reported SPAG4L-Nesprin2 meiotic complex have any function given that Sun5-null meiosis is normal?
Suggested experts: LINC complex researchers
Q: Should GO carry a specific process term for anchoring the sperm head-tail coupling apparatus to the nucleus (implantation fossa attachment)?
Suggested experts: GO editors
Experiment: Immuno-EM topology mapping of SUN5 N- and C-termini at the implantation fossa, combined with Syne3-knockout and SUN5 KASH-lid mutant knock-in mice.
Hypothesis: SUN5 anchors the coupling apparatus through a canonical SUN5-Nesprin-3 LINC complex, and disrupting the SUN-KASH interface phenocopies Sun5 loss.
Type: immuno-electron microscopy and mouse genetics
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