STIMATE

STIMATE (encoded by TMEM110) is an ER-resident multi-transmembrane protein that acts as a positive regulator of store-operated Ca²⁺ entry by physically interacting with STIM1 to promote its conformational switch and puncta formation at ER-plasma membrane junctions, driving downstream Ca²⁺-NFAT signalling (PMID:26322679). Beyond regulating individual STIM1 molecules, STIMATE maintains the long-term architecture of STIM-ORAI-competent ER-PM junctions and governs their physiological remodeling during store-dependent Ca²⁺ signalling (PMID:26644574). Its membrane engagement is mediated by a polybasic, intrinsically disordered C-terminal tail that binds PI(4,5)P₂- and PI(3,4,5)P₃-containing membranes through the residues 242VRYR245 and 284KKKK287 (PMID:35121178). STIMATE function in SOCE is antagonized by Mustn1 binding, which reduces its enhancement of SOCE and alters Orai1/STIM1 co-localization (PMID:41677464). STIMATE also operates at the lysosome, where it controls the conformational transition of the ion channel TRPML1 to generate localized Ca²⁺ efflux sites, preventing lysosomal Ca²⁺ overload, membrane disruption, and cytosolic leakage of mitochondrial DNA; its loss impairs mitochondrial clearance and exacerbates autoimmune tissue injury, with STING restraining TMEM110 expression and a TMEM110-STING interface mutation causing aberrant type I interferon activity (PMID:41540067). In addition, exosomal STIMATE secreted by alveolar epithelial cells is taken up by tissue-resident alveolar macrophages to sustain Ca²⁺ responsiveness and M2-like immunometabolic programming via the calcineurin-PGC-1α pathway (PMID:36793853).

1. 2015 High

   Established STIMATE as a dedicated positive regulator of store-operated Ca²⁺ entry, answering how STIM1 activation is potentiated at ER-PM junctions.

   Evidence Spatially restricted biotin proximity labelling/MS, BiFC, Co-IP, live-cell imaging, and Ca²⁺/NFAT reporter assays with genetic depletion

   PMID:26322679

   Open questions at the time

   • Structural basis of the STIMATE-STIM1 interaction not resolved
   • Did not define how STIMATE itself is regulated
2. 2015 High

   Showed STIMATE controls both maintenance and dynamic remodeling of ER-PM junction architecture, distinguishing a structural role from direct STIM1 binding.

   Evidence RNAi depletion with live-cell imaging of ER-PM junction dynamics and Ca²⁺ flux assays

   PMID:26644574

   Open questions at the time

   • Molecular determinants of junction tethering not mapped
   • Relationship to other junction-resident proteins unaddressed
3. 2022 High

   Defined the membrane-binding mechanism of STIMATE, showing its disordered polybasic C-terminal tail engages specific phosphoinositides via identified residues.

   Evidence Liposome pulldown, NMR spectroscopy/titration with bicelles, and site-directed mutagenesis in vitro

   PMID:35121178

   Open questions at the time

   • Functional consequence of phosphoinositide binding in cells not tested
   • Single-lab in vitro reconstitution
4. 2023 Medium

   Revealed a non-cell-autonomous, exosome-mediated role for STIMATE in shaping macrophage Ca²⁺ signalling and immunometabolism between epithelial and immune cells.

   Evidence AEC-II-specific conditional knockout mice, exosome isolation/uptake assays, Ca²⁺ and metabolic profiling, calcineurin-PGC-1α pathway analysis, bleomycin model

   PMID:36793853

   Open questions at the time

   • Mechanism of STIMATE loading into exosomes unknown
   • Single lab; how exosomal STIMATE acts in recipient cells not molecularly resolved
5. 2025 Medium

   Linked STIMATE to autophagy and osteogenic differentiation under inflammatory conditions, broadening its functional repertoire beyond Ca²⁺ junction biology.

   Evidence In vitro PDLSC osteogenesis and autophagy assays with TMEM110 knockdown/overexpression and an in vivo periodontitis model

   PMID:40065592

   Open questions at the time

   • Mechanistic link between STIMATE and autophagy machinery not defined
   • Limited mechanistic detail available
6. 2026 High

   Extended STIMATE function to the lysosome, showing it regulates TRPML1 conformation to prevent mtDNA leakage and aberrant interferon signalling, with STING as an upstream restraint.

   Evidence Conditional/genetic knockout mice, lysosomal Ca²⁺ imaging, TRPML1 conformational assays, mtDNA leakage detection, STING interface mutation analysis, TBI model

   PMID:41540067

   Open questions at the time

   • Direct physical mechanism of TRPML1 conformational control not resolved
   • How STING transcriptionally/post-transcriptionally restrains TMEM110 unclear
7. 2026 Medium

   Identified Mustn1 as a negative regulator of STIMATE-driven SOCE and a modulator of its effect on cell cycle progression.

   Evidence Overexpression of STIMATE and STIMATE-Mustn1 fusion in MEG-01/HEK293 cells, SOCE assays, Orai1/STIM1 co-localization imaging, cell cycle analysis

   PMID:41677464

   Open questions at the time

   • Endogenous Mustn1-STIMATE interaction relied on fusion overexpression
   • Mechanism by which STIMATE arrests cell cycle in G2 not defined

• How STIMATE's distinct activities at ER-PM junctions, lysosomes, and in exosomal signalling are coordinated and regulated within a single cell remains unresolved.
• No structural model integrating STIM1 and TRPML1 engagement
• Regulatory logic linking phosphoinositide binding to each functional context unknown