MVB12B is a component of the ESCRT-I complex, a heterotetrameric protein assembly comprising TSG101, VPS28, VPS37, and MVB12 proteins that mediates sorting of ubiquitinated cargo from the plasma membrane to endosomal vesicles 1. MVB12B functions as the fourth class of metazoan ESCRT-I subunits and associates with the core TSG101-VPS37 complex through conserved C-terminal sequences 1. MVB12B undergoes post-translational modifications that regulate its function. Ubiquitination of lysines 264 and 290 is induced by EGF stimulation and regulated by phosphorylation at tyrosines 241 and 243, leading to MVB12B instability and proteasomal degradation that simultaneously regulates ESCRT-I function 2. MVB12B is phosphorylated by TANK-binding kinase 1 (TBK1) in response to intracellular bacterial infection, which is essential for sorting bacterial DNA into extracellular vesicles and enabling paracrine cGAS-STING signaling in bystander cells 3. Clinically, MVB12B dysfunction is implicated in multiple diseases. Silencing MVB12B inhibits unconventional CFTRΔF508 secretion in cystic fibrosis, while MVB12B overexpression partially restores cell-surface expression and chloride channel function 4. A genetic variant (rs917778) in MVB12B is associated with reduced risk of diabetic neuropathy in type 2 diabetes patients 5, and MVB12B has been identified as a novel candidate gene for glioma susceptibility 6.