A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells.
A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells.
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DOI：
10.1080/15548627.2015.1052928
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发表时间：
2015
期刊：
影响因子：
13.3
通讯作者：
Cenci S
中科院分区：
文献类型：
--
作者：
Milan E;Perini T;Resnati M;Orfanelli U;Oliva L;Raimondi A;Cascio P;Bachi A;Marcatti M;Ciceri F;Cenci S
多发性骨髓瘤（MM）是典型的蛋白酶体抑制剂（PI）反应性癌症，但许多患者没有反应。一个有吸引力的目标，以提高敏感性是（宏观）自噬，最近发现必不可少的骨髓浆细胞，正常对应的MM。在这里，整合蛋白质组学与假设驱动的战略，我们确定了自噬货物受体和衔接蛋白，SQSTM 1/p62作为一个重要组成部分的自噬储备，不仅协同蛋白酶体维持蛋白质稳态，而且还介导了对PI的可塑性适应性反应，并忠实地报道了固有的PI敏感性。慢病毒工程揭示SQSTM 1对于MM细胞存活是必不可少的，并提供特异性PI保护。在基础条件下，SQSTM 1依赖性自噬通过组成性地处理大量的泛素化蛋白质来减轻蛋白酶体的降解负担。事实上，它的抑制或刺激大大敏感，或保护，PI诱导的蛋白质聚集和细胞死亡。此外，在蛋白酶体应激下，骨髓瘤细胞选择性地增强SQSTM 1从头表达并重置其大量内源性相互作用组，将SQSTM 1从信号传导伙伴转移到最大化其与泛素化蛋白的关联。这种自噬储备的饱和，如未消化的SQSTM 1阳性聚集体的细胞内积累所示，特异性地区分了固有地对PI敏感的患者来源的骨髓瘤与主要耐药的骨髓瘤。这些聚集体与内质网的积累相关，比较蛋白质组学将其鉴定为MM中自噬靶向的主要细胞区室。总之，这些数据将自噬整合到我们先前建立的蛋白酶体负载与容量模型中，并揭示SQSTM 1聚集作为蛋白质稳态缺陷的忠实标志物，为MM定义了一种新的预后和治疗框架。
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.