Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo 05508000, Brazil.
Institute of Clinical Biochemistry, Hannover Medical School (MHH), Carl-Neuberg-Straße, 1, 30625 Hannover, Germany.
Cells. 2021 Aug 24;10(9):2178. doi: 10.3390/cells10092178.
During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant's outcome, several strategies are being studied. We have previously shown that prolactin induces protection against proinflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat-shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1 attenuated levels of pro-apoptotic proteins such as CHOP and BIM, as well as increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and, thus, enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aimed at the optimization of beta-cell replacement therapies.
在 1 型糖尿病（T1DM）发展过程中，β细胞经历强烈的内质网（ER）应激，这可能导致未折叠蛋白反应（UPR）适应失败而发生细胞凋亡。胰岛移植被认为是 T1DM 中β细胞替代治疗的一种有吸引力的选择。为了避免移植后β细胞丢失的风险，正在研究几种策略。我们之前已经表明，催乳素通过增加热休克蛋白 B1（HSPB1）水平来诱导对抗促炎细胞因子和氧化还原失衡诱导的β细胞死亡的保护作用。由于 HSPB1 在β细胞中的作用尚未深入研究，我们研究了由内质网应激和蛋白酶体蛋白降解途径过载引起的不平衡蛋白质稳态所涉及的机制。我们测试了 HSPB1 介导的细胞保护作用是否涉及 UPR 调节以及通过泛素-蛋白酶体系统改善蛋白质降解。我们证明，HSPB1 水平的增加可降低促凋亡蛋白（如 CHOP 和 BIM）的水平，并增加蛋白质泛素化和蛋白酶体蛋白质降解的速度。我们的数据表明，HSPB1 通过增加β细胞的蛋白水解能力，诱导对蛋白毒性应激的抗性，从而增强细胞存活。这些结果可能有助于制定旨在优化β细胞替代治疗的策略。
