PDF(Pubmed)
Abstract：
Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70\'s cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.
摘要：
分子伴侣HSP70s是癌症治疗的有吸引力的靶标，但是它们的底物宽度和功能非特异性限制了它们在治疗成功中的作用.作为HSP70的伴侣，HSP40s确定HSP70s的客户特异性，并可能成为癌症治疗的更好目标。在这里，我们发现HSP40成员DNAJA2中的肿瘤缺陷受益于免疫检查点阻断（ICB）治疗。机械上,DNAJA2通过HSC70伴侣介导的自噬（CMA）及时降解关键的中心卫星蛋白PCM1和CEP290来维持中心体稳态。耗竭DNAJA2或CMA因子LAMP2A的肿瘤细胞表现出centriolar卫星蛋白水平升高，导致以异常纺锤体为特征的异常有丝分裂，染色体不分离和微核形成。这激活cGAS-STING途径以增强源自DNAJA2缺陷细胞的肿瘤中的ICB治疗应答。我们的研究揭示了DNAJA2调节有丝分裂分裂和染色体稳定性的作用，并表明DNAJA2是增强癌症免疫治疗的潜在靶标。从而为推进基于HSPs的癌症治疗提供策略。
