![]() During CMA, proteins are targeted for degradation through their interaction with a cytosolic chaperone, HSPA8/HSC70 (heat shock protein family A member 8), that recognizes and binds to a pentapeptide sequence, chemically related to the KFERQ motif, on the cargo protein. However, the process is specific and only applies to select proteins. Combined, these findings uncover cellular processes affected by CMA and reveal a new role for CMA in the control of translation in cancer cells.Ībbreviations: 6-AN: 6-aminonicotinamide ACTB: actin beta AR7: atypical retinoid 7 CHX: cycloheximide CMA: chaperone-mediated autophagy CQ: chloroquine CTS: cathepsins DDX3X: DEAD-box helicase 3 X-linked EEF2: eukaryotic translation elongation factor 2 EIF4A1: eukaryotic translation initiation factor 4A1 EIF4H: eukaryotic translation initiation factor 4H GEO: Gene Expression Omnibus GO: Gene Ontology GSEA: gene set enrichment analysis HK2: hexokinase 2 HSPA8/HSC70: heat shock protein family A (Hsp70) member 8 LAMP: lysosomal-associated membrane protein LDHA: lactate dehydrogenase A NES: normalized enrichment score NFKBIA: NFKB inhibitor alpha PCA: principle component analysis PQ: paraquat S.D.: standard deviation SUnSET: surface sensing of translation TMT: tandem mass tags TOMM40/TOM40: translocase of outer mitochondrial membrane 40.Ĭhaperone-mediated autophagy (CMA) is an important degradative mechanism that delivers intracellular components into lysosomes for cellular quality control purposes. We further show that the identified CMA substrates display high expression in multiple primary cancers compared to their normal counterparts. In particular, several proteins of the translation initiation complex were identified as bona fide CMA substrates in multiple cancer cell lines of distinct origin and we show that CMA suppresses cellular translation. Beyond verifying metabolic pathways, we show that multiple components involved in select biological processes, including cellular translation, was specifically targeted for degradation by CMA. By integrating bioinformatics analyses, we identified and categorized proteins of multiple cellular pathways that were specifically targeted by CMA. Here, we undertook a quantitative multiplex mass spectrometry approach to study the proteome of isolated lysosomes in cancer cells during CMA-activated conditions. Nearly one-third of the soluble proteins are predicted to be recognized by this pathway, yet only a minor fraction of this proteome has been identified as CMA substrates in cancer cells. Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of select soluble proteins. ![]()
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