Abstract
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.
Highlights
Pancreatic islet transplantation is an attractive alternative for the treatment of type 1 diabetes mellitus (T1DM), recommended mainly for patients suffering from frequent episodes of severe unnoticed hypoglycemia [1,2,3]
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 endoplasmic reticulum (ER) stress and overload of the proteasomal protein degradation pathway
Summary
Pancreatic islet transplantation is an attractive alternative for the treatment of T1DM, recommended mainly for patients suffering from frequent episodes of severe unnoticed hypoglycemia [1,2,3]. Results from our group have shown that PRL was able to induce the upregulation of HSPB1, a protein from the family of small heat-shock proteins (sHSPs), which turned out to be a key mediator of PRL-mediated inhibition of beta-cell apoptosis [9,10]. It is well known that proinflammatory cytokines such as interleukin 1 β (IL-1-β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) can promote beta-cell death by inducing oxidative and endoplasmic reticulum (ER) stress, as well as by promoting a reduced and inappropriate capacity to completely mount a functional autophagic response for protein degradation [15,16]. Folded proteins are retained in the ER to undergo refolding or degradation Dysregulation of these processes causes ER stress-dependent activation of the unfolded protein response (UPR), which is involved in minimizing stress and restoring homeostasis. In view of the scarce number of studies properly addressing the role of HPSB1 in beta-cells, we set out to unveil the molecular mechanisms involved in HSPB1-induced resistance to proteotoxic stress in insulin-producing cells
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