Figure 8.

Proposed mechanism of chaperone-mediated autophagy (CMA) deficiency promoting NLRP3 (NLR [NOD-like receptor] family, pyrin domain containing 3) inflammasome activation. A, In macrophages with normal CMA activity, the NLRP3 protein is degraded through the LAMP-2A (lysosome-associated membrane protein type 2A)–mediated CMA pathway, thus preventing excessive NLRP3 inflammasome activation. B, In macrophages with defective CMA, the NLRP3 protein cannot be effectively degraded and removed, resulting in excessive NLRP3 inflammasome activation and subsequent cleavage of pro–IL (interleukin)-1β and pro–IL-18 to mature IL-1β and IL-18, promoting vascular inflammation and atherosclerosis progression. ASC indicates apoptosis-associated speck-like protein containing a CARD (C-terminal caspase-recruitment domain); HSC70, heat shock cognate 71 kDa protein; and TLR, Toll-like receptor.