Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that relies on the molecular chaperone heat shock cognate 70 kDa protein (HSC70) and the lysosomal receptor LAMP-2A. By recognizing substrate proteins containing KFERQ-like pentapeptide motif, CMA plays a central role in multiple infectious contexts. In host defense and cellular homeostasis, CMA contributes to organelle quality control by selectively degrading damaged or misfolded proteins, including stress- or organelle-associated substrates, thereby limiting pathogen replication while mitigating infection-induced stress and preserving cellular function. Although its detailed mechanisms remain incompletely defined, CMA is thought to involve coordinated steps in which molecular chaperones recognize specific target sequences, recruit autophagy-related components, and deliver substrates for lysosomal translocation and degradation. Recent studies have revealed substantial progress in understanding CMA during viral, bacterial, and fungal infections, identifying key regulatory nodes and signaling pathways. These advances underscore the therapeutic potential of CMA-targeted strategies, such as stabilizing LAMP-2A or enhancing HSC70-mediated substrate recognition. However, the spatiotemporal specificity of CMA’s pro- or antiviral effects remains a major challenge for clinical translation. This review summarizes current progress in this emerging field and highlights unresolved questions, particularly whether tissue- or cell-type-specific regulation of CMA occurs during infection and how precise modulation of CMA activity might achieve optimal anti-infective outcomes.
Wang et al. (Fri,) studied this question.