LYSET (lysosomal enzyme trafficking factor; previously TMEM251, also GCAF) is a small Golgi-resident protein with two transmembrane domains that is an essential component of the mannose 6-phosphate (M6P) lysosomal enzyme targeting machinery. It binds the alpha/beta subunits of GlcNAc-1-phosphotransferase (GNPTAB) in the Golgi, stabilising the enzyme (whose beta-subunit transmembrane domain is otherwise unstable), enabling its site-1 protease cleavage and activity, and retaining it in Golgi stacks. Without LYSET, GlcNAc-1-phosphotransferase is degraded and mislocalised to lysosomes, M6P tagging is lost, soluble acid hydrolases are missorted and secreted, and lysosomal degradation of endocytic, macropinocytic and autophagic cargo fails. Biallelic LYSET loss-of-function variants cause a mucolipidosis II-like disorder, dysostosis multiplex Ain-Naz type.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | EXP PMID:33252156 Biallelic TMEM251 variants in patients with severe skeletal ... | ACCEPT | Summary: LYSET is a Golgi membrane protein. Reason: Two-transmembrane protein that co-localises with GNPTAB in Golgi stacks in several independent studies. Supporting Evidence: PMID:36074821 LYSET is a small, poorly characterized protein containing two transmembrane domains. It co-localizes with GNPTAB in the Golgi apparatus PMID:36096887 We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. |
| GO:0000139 Golgi membrane | EXP PMID:36074821 The human disease gene LYSET is essential for lysosomal enzy... | ACCEPT | Summary: LYSET is a Golgi membrane protein. Reason: Two-transmembrane protein that co-localises with GNPTAB in Golgi stacks in several independent studies. Supporting Evidence: PMID:36074821 LYSET is a small, poorly characterized protein containing two transmembrane domains. It co-localizes with GNPTAB in the Golgi apparatus PMID:36096887 We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. |
| GO:0000139 Golgi membrane | EXP PMID:36096887 GCAF(TMEM251) regulates lysosome biogenesis by activating th... | ACCEPT | Summary: LYSET is a Golgi membrane protein. Reason: Two-transmembrane protein that co-localises with GNPTAB in Golgi stacks in several independent studies. Supporting Evidence: PMID:36074821 LYSET is a small, poorly characterized protein containing two transmembrane domains. It co-localizes with GNPTAB in the Golgi apparatus PMID:36096887 We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: LYSET is a Golgi membrane protein. Reason: Two-transmembrane protein that co-localises with GNPTAB in Golgi stacks in several independent studies. Supporting Evidence: PMID:36074821 LYSET is a small, poorly characterized protein containing two transmembrane domains. It co-localizes with GNPTAB in the Golgi apparatus PMID:36096887 We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. |
| GO:0005515 protein binding | IPI PMID:36074821 The human disease gene LYSET is essential for lysosomal enzy... | REMOVE | Summary: LYSET binds GNPTAB, but 'protein binding' carries no functional information. Reason: The interaction is real (co-IP; lost with the pathogenic R45W allele) and functionally essential; its functional meaning is captured by the process terms protein stabilization and lysosomal transport. Removal does not assert the interaction is false. Supporting Evidence: PMID:36074821 These data support a model in which LYSET interacts with GNPTAB and is important for proper localization of GNPTAB in Golgi stacks. PMID:36074822 LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase |
| GO:0005794 Golgi apparatus | IDA PMID:33252156 Biallelic TMEM251 variants in patients with severe skeletal ... | ACCEPT | Summary: LYSET localises to the Golgi apparatus. Reason: Experimentally shown by immunofluorescence in human cells; consistent with its role retaining GNPTAB in the Golgi. Supporting Evidence: PMID:33252156 Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. PMID:36074821 LYSET is a small, poorly characterized protein containing two transmembrane domains. It co-localizes with GNPTAB in the Golgi apparatus |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | ACCEPT | Summary: LYSET localises to the Golgi apparatus. Reason: Experimentally shown by immunofluorescence in human cells; consistent with its role retaining GNPTAB in the Golgi. Supporting Evidence: PMID:33252156 Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. PMID:36074821 LYSET is a small, poorly characterized protein containing two transmembrane domains. It co-localizes with GNPTAB in the Golgi apparatus |
| GO:0007040 lysosome organization | IMP PMID:36096887 GCAF(TMEM251) regulates lysosome biogenesis by activating th... | KEEP AS NON CORE | Summary: LYSET loss impairs lysosome biogenesis as a consequence of failed hydrolase delivery. Reason: Accurate but downstream of the core role in maintaining GlcNAc-1-phosphotransferase and M6P-dependent enzyme targeting. Supporting Evidence: PMID:36096887 Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. |
| GO:0007041 lysosomal transport | IMP PMID:36074821 The human disease gene LYSET is essential for lysosomal enzy... | ACCEPT | Summary: LYSET is required for transport of soluble hydrolases to lysosomes via the M6P pathway. Reason: LYSET loss causes global loss of M6P tagging and missorting/depletion of lysosomal enzymes in several independent knockout systems. Supporting Evidence: PMID:36074821 LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. PMID:36074822 Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. PMID:36096887 Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. |
| GO:0007041 lysosomal transport | IMP PMID:36074822 Lysosomal enzyme trafficking factor LYSET enables nutritiona... | ACCEPT | Summary: LYSET is required for transport of soluble hydrolases to lysosomes via the M6P pathway. Reason: LYSET loss causes global loss of M6P tagging and missorting/depletion of lysosomal enzymes in several independent knockout systems. Supporting Evidence: PMID:36074821 LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. PMID:36074822 Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. PMID:36096887 Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. |
| GO:0031985 Golgi cisterna | IDA PMID:36074821 The human disease gene LYSET is essential for lysosomal enzy... | ACCEPT | Summary: LYSET co-localises with GNPTAB in Golgi stacks/cisternae. Reason: The full-text immunofluorescence data place LYSET with GNPTAB in Golgi stacks; this is a more specific acceptable location. Supporting Evidence: PMID:36074821 These data support a model in which LYSET interacts with GNPTAB and is important for proper localization of GNPTAB in Golgi stacks. |
| GO:0060627 regulation of vesicle-mediated transport | IMP PMID:36074822 Lysosomal enzyme trafficking factor LYSET enables nutritiona... | MARK AS OVER ANNOTATED | Summary: Impaired turnover of macropinocytic cargo in LYSET-deficient cells reflects lysosomal hydrolase depletion, not regulation of vesicle trafficking. Reason: The paper attributes the cargo-turnover defect to depletion of lysosomal enzymes ('Consequently ...'), so a regulatory role in vesicle-mediated transport is not supported. Supporting Evidence: PMID:36074822 Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. |
| GO:0050821 protein stabilization | IMP PMID:36074822 Lysosomal enzyme trafficking factor LYSET enables nutritiona... | NEW | Summary: LYSET is required to stabilise GlcNAc-1-phosphotransferase (GNPTAB) in the Golgi. Reason: In LYSET-deficient cells GlcNAc-1-phosphotransferase is unstable and degraded; LYSET binds it directly, and the pathogenic R45W allele that fails to bind does not rescue GNPTAB levels. LYSET itself does the stabilising work (binding the enzyme's hydrophilic transmembrane segment), so this is participation, not mere necessity. Supporting Evidence: PMID:36074822 Without LYSET, GlcNAc-1-phosphotransferase was unstable because of a hydrophilic transmembrane domain. PMID:36074822 LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase |
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Download this section (compressed HTML)Q: Does LYSET act as a chaperone that shields the hydrophilic GNPTAB beta-subunit transmembrane domain, and should GO represent this with a molecular function term?
Suggested experts: lysosomal enzyme trafficking biochemists, GO molecular function editors
Experiment: Reconstitute GNPTAB with wild-type or R45W LYSET in proteoliposomes and measure GNPTAB stability, S1P cleavage and GlcNAc-1-phosphotransferase activity.
Hypothesis: LYSET directly stabilises the GNPTAB transmembrane region, which is sufficient for S1P cleavage and activity.
Type: biochemical reconstitution
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