HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells.

Gomes, Vinícius M ORCID; Wailemann, Rosangela A M ORCID; Arini, Gabriel S ORCID; Oliveira, Talita C; Almeida, Daria R Q; Dos Santos, Ancély F ORCID; Terra, Leticia F.; Lortz, Stephan ORCID; Labriola, Leticia ORCID

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.

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Gomes, Vinícius / Wailemann, Rosangela / Arini, Gabriel / et al: HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells.. 2021.

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