TMEM268

TMEM268 is a transmembrane protein that functions as a stabilizer of integrin subunits, preventing their degradation and thereby supporting integrin-dependent cytoskeletal signaling and phagocyte function (PMID:30361615, PMID:38730209). In epithelial/cancer cells, TMEM268 binds integrin β4 (ITGB4) through a C-terminal interaction and protects it from ubiquitin-mediated degradation; loss of TMEM268 destabilizes ITGB4 and filamin A, dissociates the ITGB4/PLEC complex, and disrupts cytoskeleton remodeling, with consequences for proliferation, adhesion, and tumorigenesis (PMID:30361615). In phagocytes, TMEM268 binds the β2 integrin subunit CD11b (integrin αM) and inhibits its endosome-lysosome-mediated degradation, and its loss impairs phagocyte adhesion, migration, and complement-dependent phagocytosis, worsening sepsis in vivo (PMID:38730209). Beyond these two integrin-stabilizing roles, no further mechanistic detail has been characterized in the available corpus.

1. 2018 High

   Established the first molecular function for TMEM268 by showing it binds and stabilizes the integrin subunit ITGB4, linking it to cytoskeletal signaling and tumor biology.

   Evidence Reciprocal Co-IP with C-terminal interaction mapping, TMEM268 knockout cell lines, ubiquitination assays, and xenograft tumor models

   PMID:30361615

   Open questions at the time

   • Identity of the E3 ligase mediating ITGB4 ubiquitination not defined
   • No structural model of the TMEM268 C-terminus-ITGB4 interface
   • Membrane topology and subcellular site of the stabilization event not resolved
2. 2024 High

   Extended TMEM268 function to immune cells, showing it stabilizes the β2 integrin subunit CD11b by blocking endosome-lysosome degradation and is required for phagocyte-mediated anti-infectious responses.

   Evidence Co-IP for the TMEM268-CD11b interaction, Tmem268 knockout mice, cecal ligation and puncture sepsis model, and phagocyte adhesion/migration and complement-dependent phagocytosis assays

   PMID:38730209

   Open questions at the time

   • Whether ITGB4 and CD11b stabilization share a common molecular mechanism not addressed
   • The degradation machinery (specific endosomal/lysosomal route) directing CD11b not detailed
   • Direct versus indirect nature of the TMEM268-CD11b binding not fully dissected

• Whether TMEM268 acts as a general integrin chaperone/stabilizer across additional integrin subunits, and the precise biochemical mechanism by which it shields partners from degradation, remains unresolved.
• No defined enzymatic or adaptor activity for the stabilization mechanism
• No structural characterization of the protein
• Breadth of integrin partners beyond ITGB4 and CD11b unknown