TMEM9B is a glycosylated transmembrane protein localized to lysosomal and early endosomal membranes 1 that functions as an obligatory β-subunit for endosomal chloride/proton exchangers ClC-3, ClC-4, and ClC-5 23. TMEM9B enhances production of pro-inflammatory cytokines induced by TNF, IL-1β, and TLR ligands 1. Mechanistically, it acts downstream of RIP1 and upstream of MAPK and IκB kinases at the level of the TAK1 complex, playing an essential role in TNF activation of both NF-κB and MAPK signaling pathways 1. At the molecular level, TMEM9B inhibits CLC-3 by sealing the cytosolic chloride ion pathway entrance, with this inhibition stabilized by phosphatidylinositol 3,5-bisphosphate 2. This tonic inhibition prevents pathological chloride accumulation and endosomal swelling 3. TMEM9B is not required for TNF- or Fas ligand-induced apoptosis 1. Dysregulation of TMEM9B methylation has been associated with coronary heart disease and atrial fibrillation pathogenesis 45. These findings indicate TMEM9B is a critical regulator of inflammatory signaling and endosomal ion homeostasis, suggesting therapeutic potential in inflammatory and cardiovascular diseases.