ARMH3 (C10orf76) is a 689-residue armadillo-like helical protein that cycles between the cytosol and the trans-Golgi network. It is an effector of the small GTPase ARL5, binding its GTP-bound form, and it forms a heterodimer with phosphatidylinositol 4-kinase III beta (PI4KB). The interface has been mapped to the PI4KB kinase linker and also depends on an N-terminal PI4KB helix. ARMH3 promotes PI4KB-dependent synthesis of the main PI4P pool at the TGN. That pool recruits GOLPH3, supports CERT-mediated ceramide transfer to the distal Golgi, and maintains Golgi organization. After cGAMP stimulation, ARMH3 binds STING at the Golgi and recruits PI4KB, generating the PI4P that routes STING to endosomes for full activation. ARMH3 is also needed for replication of certain enteroviruses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IDA PMID:31519766 BioID Performed on Golgi Enriched Fractions Identify C10orf7... | ACCEPT | Summary: Golgi membrane (IDA). ARMH3 is recruited to the trans-Golgi network by active ARL5 and by PI4KB, and it cycles on and off GBF1-positive Golgi membranes. Core location. Reason: [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] [PMID:31829496 "Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses."] [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] Supporting Evidence: PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. PMID:31829496 Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses. PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi membrane (IEA). ARMH3 is recruited to the trans-Golgi network by active ARL5 and by PI4KB, and it cycles on and off GBF1-positive Golgi membranes. Core location. Reason: [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] [PMID:31829496 "Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses."] [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] Supporting Evidence: PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. PMID:31829496 Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses. PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. |
| GO:0005515 protein binding | IPI PMID:23572552 ACBD3 interaction with TBC1 domain 22 protein is differentia... | MODIFY | Summary: Protein binding (IPI) with PI4KB. ARMH3 forms a heterodimer with PI4KB, and ARMH3 bridges PI4KB to its Golgi partners (ARL5, STING) to drive TGN PI4P synthesis. HDX-MS maps binding to the PI4KB kinase linker, while an N-terminal PI4KB helix mutation (QE65AA) also abolishes binding. Recruitment is mutual: PI4KB is needed for ARMH3's Golgi localization, and ARMH3 recruits PI4KB. Modified to protein-membrane adaptor activity, as for the same row in the ACBD3 review. Reason: [PMID:31829496 "We used hydrogen-deuterium exchange mass spectrometry to characterize the c10orf76-PI4KB complex and reveal that binding is mediated by the kinase linker of PI4KB, with formation of the heterodimeric complex modulated by PKA-dependent phosphorylation."] [PMID:23572552 "Mutant QE65AA abrogated binding of PI4KB to C10orf76 and Rab11B but increased binding to ACBD3 by 6-fold."] [PMID:31829496 "Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses."] [PMID:36921576 "Thus, ARMH3 bridges STING and PIK4B to generate PI4P for STING transportation and activation, an interaction conserved in all eukaryotes."] Proposed replacements: protein-membrane adaptor activity Supporting Evidence: PMID:31829496 We used hydrogen-deuterium exchange mass spectrometry to characterize the c10orf76-PI4KB complex and reveal that binding is mediated by the kinase linker of PI4KB, with formation of the heterodimeric complex modulated by PKA-dependent phosphorylation. PMID:23572552 Mutant QE65AA abrogated binding of PI4KB to C10orf76 and Rab11B but increased binding to ACBD3 by 6-fold. PMID:31829496 Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses. PMID:36921576 Thus, ARMH3 bridges STING and PIK4B to generate PI4P for STING transportation and activation, an interaction conserved in all eukaryotes. |
| GO:0005515 protein binding | IPI PMID:31519766 BioID Performed on Golgi Enriched Fractions Identify C10orf7... | REMOVE | Summary: Protein binding (IPI) with GBF1, from BioID on Golgi-enriched fractions. ARMH3 interacts with the ARF GEF GBF1 and cycles on and off GBF1-positive Golgi structures. No specific MF term captures this association; removed under the generic protein-binding policy. Removal does not mean the interaction is false. Reason: Removed under the generic protein-binding policy. The interaction itself is reported: [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] Supporting Evidence: PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. |
| GO:0005737 cytoplasm | EXP PMID:31519766 BioID Performed on Golgi Enriched Fractions Identify C10orf7... | KEEP AS NON CORE | Summary: Cytoplasm (EXP). ARMH3 has a soluble pool that cycles on and off Golgi membranes; its site of action is the trans-Golgi network. Kept as non-core. Reason: [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] Supporting Evidence: PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm (IEA). ARMH3 has a soluble pool that cycles on and off Golgi membranes; its site of action is the trans-Golgi network. Kept as non-core. Reason: [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] Supporting Evidence: PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | ACCEPT | Summary: Golgi apparatus (IEA). ARMH3 is recruited to the trans-Golgi network by active ARL5 and by PI4KB, and it cycles on and off GBF1-positive Golgi membranes. Core location. Reason: [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] [PMID:31829496 "Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses."] [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q6PD19 SUPPORTS TRANSFER Mouse Armh3 (UniProtKB:Q6PD19); a one-to-one ortholog. The human protein has direct Golgi evidence (PMID:31519766, PMID:39580461). Supporting Evidence: PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. PMID:31829496 Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses. PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cytosol (IBA). ARMH3 has a soluble pool that cycles on and off Golgi membranes; its site of action is the trans-Golgi network. Kept as non-core. Reason: [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001006532 SUPPORTS TRANSFER ARMH3 node; its only seed is human ARMH3 itself (UniProtKB:Q5T2E6), with cytosol IDA from PMID:31519766. Supporting Evidence: PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. |
| GO:0005829 cytosol | IDA PMID:31519766 BioID Performed on Golgi Enriched Fractions Identify C10orf7... | KEEP AS NON CORE | Summary: Cytosol (IDA). ARMH3 has a soluble pool that cycles on and off Golgi membranes; its site of action is the trans-Golgi network. Kept as non-core. Reason: [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] Supporting Evidence: PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perinuclear region of cytoplasm (IEA, from mouse Armh3). ARMH3 acts at the Golgi and trans-Golgi network, which sit in the perinuclear region of most cultured cells. The precise location is captured by the Golgi rows; kept as non-core. Reason: [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] [PMID:31519766 "We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q6PD19 SUPPORTS TRANSFER Mouse Armh3 (UniProtKB:Q6PD19); a one-to-one ortholog. The human protein has direct Golgi evidence (PMID:31519766, PMID:39580461). Supporting Evidence: PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. PMID:31519766 We find that C10orf76 interacts with GBF1 and rapidly cycles on and off GBF1-positive Golgi structures. |
| GO:1903358 regulation of Golgi organization | IMP PMID:31519766 BioID Performed on Golgi Enriched Fractions Identify C10orf7... | ACCEPT | Summary: Regulation of Golgi organization (IMP). ARMH3 knockdown fragments the Golgi, and ARMH3 sustains the TGN PI4P pool that organizes Golgi trafficking. Accepted. Reason: [PMID:31519766 "Knockdown studies revealed C10orf76 to be involved in Golgi maintenance."] [PMID:39580461 "Instead, ARMH3 functions to activate phosphatidylinositol 4-kinase IIIΞ² (PI4KB), accounting for the main pool of phosphatidylinositol 4-phosphate (PI4P) at the TGN."] Supporting Evidence: PMID:31519766 Knockdown studies revealed C10orf76 to be involved in Golgi maintenance. PMID:39580461 Instead, ARMH3 functions to activate phosphatidylinositol 4-kinase IIIΞ² (PI4KB), accounting for the main pool of phosphatidylinositol 4-phosphate (PI4P) at the TGN. |
| GO:0090218 positive regulation of lipid kinase activity | IMP PMID:39580461 ARMH3 is an ARL5 effector that promotes PI4KB-catalyzed PI4P... | NEW | Summary: Positive regulation of lipid kinase activity (NEW, IMP). Knocking out ARMH3 sharply reduces PI4P at the Golgi, as does loss of PI4KB itself. ARMH3 activates PI4KB to produce the main TGN PI4P pool. Activation is shown in cells, not with purified components, so this is a regulation term rather than an activator MF. Reason: [PMID:39580461 "Remarkably, knocking out ARL5, its upstream activators ARFRP1 or SYS1, or ARMH3 also led to a drastic reduction in PI4P staining at the Golgi complex (Fig."] [PMID:39580461 "Instead, ARMH3 functions to activate phosphatidylinositol 4-kinase IIIΞ² (PI4KB), accounting for the main pool of phosphatidylinositol 4-phosphate (PI4P) at the TGN."] Supporting Evidence: PMID:39580461 Remarkably, knocking out ARL5, its upstream activators ARFRP1 or SYS1, or ARMH3 also led to a drastic reduction in PI4P staining at the Golgi complex (Fig. PMID:39580461 Instead, ARMH3 functions to activate phosphatidylinositol 4-kinase IIIΞ² (PI4KB), accounting for the main pool of phosphatidylinositol 4-phosphate (PI4P) at the TGN. |
| GO:0031267 small GTPase binding | IDA PMID:39580461 ARMH3 is an ARL5 effector that promotes PI4KB-catalyzed PI4P... | NEW | Summary: Small GTPase binding (NEW, IDA). ARMH3 binds GTP-bound but not GDP-bound ARL5, and is recruited to the TGN by the SYS1-ARFRP1-ARL5 cascade; it is an ARL5 effector. Reason: [PMID:39580461 "Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner."] Supporting Evidence: PMID:39580461 Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. |
| GO:0141111 positive regulation of cGAS/STING signaling pathway | IMP PMID:36921576 ARMH3-mediated recruitment of PI4KB directs Golgi-to-endosom... | NEW | Summary: Positive regulation of cGAS/STING signaling pathway (NEW, IMP). A genome-wide CRISPR screen identified ARMH3 as critical for STING activation. After cGAMP stimulation, ARMH3 binds STING at the Golgi and recruits PI4KB to make the PI4P that sends STING to endosomes. ARMH3 performs the recruitment step itself. Reason: [PMID:36921576 "A genome-wide CRISPR-Cas9 screen identified Armadillo-like helical domain-containing protein 3 (ARMH3) as critical for STING activation."] [PMID:36921576 "Upon cGAMP-triggered translocation, ARMH3 interacted with STING at the Golgi and recruited phosphatidylinositol 4-kinase beta (PI4KB) to synthesize PI4P, which directed STING Golgi-to-endosome trafficking via PI4P-binding proteins AP-1 and GGA2."] Supporting Evidence: PMID:36921576 A genome-wide CRISPR-Cas9 screen identified Armadillo-like helical domain-containing protein 3 (ARMH3) as critical for STING activation. PMID:36921576 Upon cGAMP-triggered translocation, ARMH3 interacted with STING at the Golgi and recruited phosphatidylinositol 4-kinase beta (PI4KB) to synthesize PI4P, which directed STING Golgi-to-endosome trafficking via PI4P-binding proteins AP-1 and GGA2. |
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Download this section (compressed HTML)Q: Does ARMH3 stimulate PI4KB catalytic activity directly, or only by positioning it at the TGN? The cited studies report no purified-component kinase assay with ARMH3.
Q: Is the CERT-preferred distal-Golgi PI4P pool specific to ARMH3, distinct from the ACBD3-recruited PI4KB pool?
Q: Is ARMH3-PI4KB recruitment sequential or mutual, given that each is reported to be needed for the other's Golgi localization?
Experiment: Reconstitute PI4KB activity on liposomes with purified ARMH3 and GTP-ARL5 to test direct activation.
Experiment: Rescue ARMH3-KO cells with a PI4KB-binding-deficient ARMH3 and measure Golgi PI4P, CERT ceramide transfer and STING trafficking.
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