TMEM167A

TMEM167A (Kish) is a small, conserved membrane protein that functions as an essential component of the early secretory pathway, required for anterograde cargo transport from the ER to the Golgi (PMID:19942856, PMID:40924476). It was first identified in a genome-wide screen as a metazoan-specific secretory factor whose loss blocks regulated protein secretion (PMID:19942856), and it acts cell-autonomously in JNK-dependent unconventional secretion, including the release of Tyrosyl-tRNA synthetase during Drosophila cell competition (PMID:26658841). Beyond bulk secretion, TMEM167A governs downstream vesicular trafficking: its loss expands recycling endosomes, depletes lysosomes, impairs intracellular vesicle acidification and autophagy, and reroutes EGFR from recycling toward proteasomal degradation, thereby restraining glioma growth (PMID:30506943, PMID:31947645). TMEM167A forms a complex with IER3IP1 that limits IRE1α/XBP1-mediated unfolded protein response activation (PMID:37934820). In pancreatic β cells, TMEM167A is required for proinsulin trafficking from the ER to the Golgi, and biallelic loss-of-function variants (including p.Val59Glu) sensitize β cells to ER stress and cause β cell dysfunction, establishing a causal link to a neonatal-diabetes–microcephaly–epilepsy (MEDS) syndrome (PMID:40924476).

1. 2009 High

   Established that TMEM167A/Kish is a bona fide component of the metazoan secretory pathway, defining its core cellular role for the first time.

   Evidence Genome-wide RNAi screen in Drosophila S2 cells with a secreted-luciferase readout

   PMID:19942856

   Open questions at the time

   • Did not define the molecular step (ER exit, ER-to-Golgi, or later) at which Kish acts
   • No interacting partners or biochemical mechanism identified
   • No mammalian validation in the founding study
2. 2015 Medium

   Placed TMEM167A in JNK-dependent unconventional secretion, extending its role beyond constitutive secretion to signal-driven cargo release in vivo.

   Evidence Drosophila kish RNAi in loser cells with haemocyte-recruitment assays and JNK epistasis

   PMID:26658841

   Open questions at the time

   • Mechanism by which kish couples to JNK signaling not resolved
   • Whether the same secretory machinery operates in mammalian cells untested
   • Single laboratory
3. 2018 Medium

   Showed TMEM167A controls endosomal compartment balance and EGFR fate, linking the secretory factor to receptor trafficking and tumor growth.

   Evidence RNAi knockdown in Drosophila and human glioma cells with endosomal/lysosomal imaging and EGFR localization/degradation assays

   PMID:30506943

   Open questions at the time

   • Direct molecular mechanism linking TMEM167A loss to recycling-vs-degradation switch unknown
   • No reconstitution of TMEM167A activity on EGFR
   • Single laboratory
4. 2020 Medium

   Connected TMEM167A loss to defective vesicle acidification and autophagy, implicating V-ATPase-dependent compartment function in its EGFR-trafficking role.

   Evidence siRNA knockdown in wild-type p53 glioma cells with vesicle-pH, autophagy and EGFR readouts, plus V-ATPase inhibitor phenocopy and tumor growth assays

   PMID:31947645

   Open questions at the time

   • Whether TMEM167A acts directly on V-ATPase or upstream of vesicle maturation unclear
   • p53 context-dependence not mechanistically explained
   • Single laboratory
5. 2023 Medium

   Identified a physical TMEM167A–IER3IP1 complex that restrains IRE1α/XBP1 UPR signaling, giving TMEM167A a defined partner and a role in ER stress homeostasis.

   Evidence ENU forward genetic screen in mice plus co-immunoprecipitation and IRE1α/XBP1 UPR readouts in primary B cells

   PMID:37934820

   Open questions at the time

   • Stoichiometry and structure of the TMEM167A–IER3IP1 complex unknown
   • How the complex mechanistically dampens IRE1α activation not resolved
   • Single laboratory
6. 2025 High

   Established TMEM167A as essential for proinsulin ER-to-Golgi trafficking and as a causative gene for a neonatal-diabetes–microcephaly–epilepsy syndrome via biallelic loss-of-function variants.

   Evidence siRNA in EndoC-βH1 cells, CRISPR knock-in of p.Val59Glu in iPSC-derived β cells, trafficking and ER-stress assays, and genome sequencing of MEDS patients

   PMID:40924476

   Open questions at the time

   • Molecular function of TMEM167A in the ER-exit/Golgi-entry step not defined at the protein level
   • Mechanism of neuronal vulnerability underlying microcephaly/epilepsy not dissected
   • Whether the IER3IP1 complex mediates the proinsulin trafficking role untested

• The biochemical activity of TMEM167A within ER-to-Golgi transport — its direct molecular function, cargo-recognition or vesicle-budding role, and structural basis of the IER3IP1 interaction — remains undefined.
• No enzymatic or transport activity assigned
• No structural model of TMEM167A or its complexes
• Mechanism coupling secretory function to ER-stress suppression unresolved