期刊
AUTOPHAGY
卷 11, 期 7, 页码 1161-1178出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1052928
关键词
aggregate; autophagy; bortezomib; endoplasmic reticulum; multiple myeloma; p62; plasma cells; proteasome; proteasome inhibitors; proteostasis; SQSTM1; ubiquitin; Ab; antibody; amc; 7-amino-4-methylcoumarin; APC; allophycocyanin; Baf A1; bafilomycin A(1); Btz; bortezomib; BM; bone marrow; ER; endoplasmic reticulum; ERGIC; ER-Golgi intermediate compartment; GO; gene ontology; HCQ; hydroxychloroquine; Ig; immunoglobulin; IP; immunoprecipitation; LC-MS; MS; liquid chromatography-tandem mass spectrometry; MM; multiple myeloma; pAb; polyclonal antibody; PBS; phosphate-buffered saline; PC; plasma cell; PI; proteasome inhibitor; Rapa; rapamycin; SILAC; stable isotope labeling in cell culture; Ub; ubiquitin; UPR; unfolded protein response; UPS; ubiquitin-proteasome system
类别
资金
- Multiple Myeloma Research Foundation
- Italian Ministry of Health [1143560]
- Italian Association for Cancer Research (AIRC) [14691, 9965]
Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis-driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1-dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load-versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM.
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