ARMH3

ARMH3 (C10orf76/DGARM) is an armadillo-repeat protein that organizes phosphatidylinositol 4-phosphate (PI4P) production at the trans-Golgi network to drive downstream membrane trafficking, lipid transport, and innate immune signaling (PMID:39580461, PMID:36921576). It is recruited to the TGN as an effector of the active GTPase ARL5, binding GTP-bound but not inactive ARL5 in a SYS1-ARFRP1-ARL5-dependent manner (PMID:39580461). At the Golgi, ARMH3 forms a heterodimeric complex with PI4KB by binding the PI4KB kinase linker region, an interaction modulated by PKA-dependent phosphorylation of PI4KB; this complex is required both for ARMH3 membrane recruitment and for Golgi PI4P levels (PMID:31829496). Through this PI4KB-dependent PI4P pool, ARMH3 promotes recruitment of the oncoprotein GOLPH3 and TGN glycan modifications (PMID:39580461), and supplies a distal-Golgi PI4P pool preferentially used by the ceramide transport protein CERT for ER-to-Golgi ceramide trafficking (PMID:37195633). In innate immunity, ARMH3 interacts with STING at the Golgi upon cGAMP stimulation and recruits PI4KB to generate PI4P that directs STING Golgi-to-endosome trafficking via AP-1 and GGA2; disruption of the ARMH3-PI4KB-PI4P axis impairs STING activation, and Armh3-deficient mice are susceptible to DNA virus challenge (PMID:36921576). ARMH3 also interacts with the ARF GEF GBF1 and contributes to Arf1 activation, with its depletion causing Golgi fragmentation and impaired secretion (PMID:31829496, PMID:31519766), while its function is distinct from GARP-mediated endosome-to-TGN retrograde transport (PMID:39580461).

1. 2019 High

   Established the core biochemical interaction underlying ARMH3 function: that it directly binds and partners PI4KB, defining the molecular basis for its role in Golgi PI4P generation.

   Evidence HDX-MS, complex-disrupting mutagenesis, and biochemical binding assays mapping the PI4KB kinase linker interface and PKA-phosphorylation modulation

   PMID:31829496

   Open questions at the time

   • No high-resolution structure of the heterodimer
   • Functional consequence of PKA-modulated assembly on PI4P output not quantified
2. 2019 High

   Showed the ARMH3-PI4KB complex is functionally required, linking complex integrity to Golgi PI4P levels, ARMH3 membrane recruitment, and enterovirus replication.

   Evidence Complex-disrupting mutations with Golgi PI4P measurements, localization microscopy, and viral replication assays

   PMID:31829496

   Open questions at the time

   • Mechanism by which PI4KB recruits ARMH3 to membranes not resolved
   • Range of enteroviruses dependent on ARMH3 incompletely defined
3. 2019 Medium

   Placed ARMH3 in Golgi maintenance machinery by linking it to GBF1 and Arf1 activation, providing a candidate mechanism for its effect on PI4P and secretion.

   Evidence BioID, Co-IP, live-cell imaging, and RNAi knockdown with Golgi morphology, secretion, and Arf1 activation readouts

   PMID:31519766 PMID:31829496

   Open questions at the time

   • Arf1 activation effect supported by a single knockdown assay described as putative
   • Direct vs indirect nature of the GBF1-ARMH3 interaction not dissected
4. 2023 High

   Connected the ARMH3-PI4KB-PI4P axis to innate immunity, showing ARMH3 controls STING Golgi-to-endosome trafficking and antiviral defense in vivo.

   Evidence Genome-wide CRISPR screen, ARMH3-STING Co-IP, RNAi of PI4P-binding adaptors, PI4P measurements, STING trafficking assays, and Armh3fl/fl;LyzCre mice challenged with DNA virus

   PMID:36921576

   Open questions at the time

   • Whether STING binding is direct or PI4P-mediated not fully separated
   • Spatial coupling of ARMH3-STING engagement to ARL5 recruitment unaddressed
5. 2023 High

   Demonstrated that ARMH3 generates a spatially distinct distal-Golgi PI4P pool dedicated to CERT-mediated ceramide transport, distinguishing it from the ACBD3-recruited PI4KB pool.

   Evidence Genome-wide screening, super-resolution microscopy, and KO/KD of PI4KB, ACBD3, and C10orf76 with ceramide trafficking assays

   PMID:37195633

   Open questions at the time

   • Molecular basis for spatial segregation of PI4P pools unresolved
   • How CERT preferentially reads the ARMH3-dependent pool not defined
6. 2024 High

   Defined the upstream recruitment logic, establishing ARMH3 as a GTP-dependent ARL5 effector whose TGN localization drives the dominant TGN PI4P pool and downstream GOLPH3/glycosylation, while excluding a GARP-like retrograde role.

   Evidence BioID, GTP-dependent interaction and genetic epistasis through SYS1-ARFRP1-ARL5, plus KO with PI4P, GOLPH3, glycan, and retrograde cargo readouts

   PMID:39580461

   Open questions at the time

   • How ARL5-dependent recruitment integrates with PI4KB-dependent recruitment not reconciled
   • Direct effect on glycan-modifying enzymes vs indirect PI4P effect unclear

• How ARMH3 spatially and temporally coordinates its distinct PI4P-dependent outputs (STING trafficking, CERT ceramide transport, GOLPH3 recruitment, glycosylation, enterovirus replication) from a single PI4KB-binding activity remains unresolved.
• No structural model integrating ARL5, GBF1, and PI4KB engagement
• Mechanism partitioning PI4P pools between competing effectors unknown