The ubiquitin-proteasome system and autophagy: self-digestion for metabolic health.

Type 2 diabetes mellitus (T2DM) is a global health challenge. Therefore, understanding the molecular mechanisms underlying the pathophysiology of T2DM is key to improving current therapies. Loss of protein homeostasis leads to the accumulation of damaged proteins in cells, which results in tissue dysfunction. The elimination of damaged proteins occurs through the ubiquitin-proteasome system (UPS) and autophagy. In this review, we describe the mutual regulation between the UPS and autophagy and the involvement of these two proteolytic systems in metabolic dysregulation, insulin resistance, and T2DM. We propose that alterations in the UPS or autophagy contribute to triggering insulin resistance and the development of T2DM. In addition, these two pathways emerge as promising therapeutic targets for improving insulin resistance.

The dialogue between the ubiquitin-proteasome system and autophagy: Implications in ageing.

Dysregulated proteostasis is one of the hallmarks of ageing. Damaged proteins may impair cellular function and their accumulation may lead to tissue dysfunction and disease. This is why protective mechanisms to safeguard the cell proteome have evolved. These mechanisms consist of cellular machineries involved in protein quality control, including regulators of protein translation, folding, trafficking and degradation. In eukaryotic cells, protein degradation occurs via two main pathways: the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Although distinct pathways, they are not isolated systems and have a complementary nature, as evidenced by recent studies. These findings raise the question of how autophagy and the proteasome crosstalk. In this review we address how the two degradation pathways impact each other, thereby adding a new layer of regulation to protein degradation. We also analyze the implications of the UPS and autophagy in ageing.

Influence of the Insertion Method of Aryl-Extended Calix[4]pyrroles into Liposomal Membranes on Their Properties as Anion Carriers.

We disclose the results of our investigations on the influence that the insertion method of aryl-extended calix[4]pyrrole into liposomal membranes exerts on their properties as anion carriers. We use the standard HPTS assay to assess the transport properties of the carriers. We show that the post-insertion of the carrier, as DMSO solution, assigns better transport activities to the "two-wall" α,α-aryl-extended calix[4]pyrrole 1 compared to the "four-wall" α,α,α,α-counterpart 2. Notably, opposite results were obtained when the carriers were pre-inserted into the liposomal membranes. We assign this difference to an improved incorporation of carrier 2 into the membrane when delivered by the pre-insertion method. On the other hand, carrier 1 shows comparable levels of transport independently of the method used for its incorporation. Thus, an accurate comparison of the chloride transport activities featured by these two carriers demands their pre-incorporation in the liposomal membranes. In contrast, using the lucigenin assay with the pre-insertion method both carriers displayed similar transport efficiencies.