CHMP2B (charged multivesicular body protein 2B) is a core component of the ESCRT-III complex that mediates critical membrane fission events in cellular trafficking and cytokinesis 1. The protein functions in autophagy, endolysosomal trafficking, and multivesicular body formation by recruiting the AAA-ATPase Vps4 for membrane abscission 1. CHMP2B undergoes post-translational regulation through SMYD2-mediated methylation at lysine 6, which controls its polymerization dynamics and timing of cytokinetic abscission 2. The protein also participates in ESCRT-III assembly through interactions with YAP1 and VPS4B, promoting autophagosome formation 3. Disease-associated mutations, particularly CHMP2BIntron5, cause C-terminal truncation that removes the Vps4 binding site and disrupts autoinhibition, leading to frontotemporal dementia (FTD-3) 1. In sporadic ALS, CHMP2B promotes pathological CHMP7-mediated nuclear pore complex injury, contributing to TDP-43 dysfunction 4. The protein's dysfunction converges with other ALS-associated genes in vesicle trafficking pathways, highlighting mechanistic overlap in neurodegeneration 5. CHMP2B represents a critical node in cellular membrane dynamics, with mutations causing autophagy impairment and neurodegeneration through both gain- and loss-of-function mechanisms 6.