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Dysfunction at cell junctions ages fruit fly renal tubules

Cell–cell junctional integrity is particularly important for the function of epithelial tissues, but is compromised in ageing, leading to dysfunction of epithelial barriers at the cellular and tissue levels. Here (Dornan et al., 2023), Julian Dow and colleagues model age-related dysfunction in the Drosophila melanogaster Malpighian tubules, the fruit fly equivalent of mammalian kidneys, by knocking down expression of the occluding (septate) junction protein Snakeskin (Ssk) in renal secretory cells. Loss of Ssk expression in the Malpighian tubule induces progressive renal dysfunction as a consequence of disrupted septate junction organization between cells. At the cellular level, the authors find that junctional failure is associated with actin cytoskeleton disorganization and loss of apicobasal polarity, which is crucial for maintaining renal solute transport and organismal fluid homeostasis. Further, Malpighian tubule tissue organization is compromised in this model through apparent hyperplasia of renal stem cells and breakdown of paracellular barriers, cumulatively resulting in not only tissue-level renal dysfunction but also increased invasion of bacteria in the Malpighian tubule lumen. Strikingly, these effects might phenocopy effects of ageing on Malpighian tubules in wild-type flies. Going forward, the possible ‘accelerated ageing’ of the Malpighian tubules in this model could help better dissect the sequence of cellular events in epithelial tissues that lead to age-related homeostatic decline and loss of barrier integrity.

Derlins and Surf4 work together to ERADicate COX-2

Cyclooxygenase-2 (COX-2) is a crucial enzyme in the synthesis of eicosanoids, signalling molecules that regulate a broad array of physiological processes. COX-2 is dynamically regulated in response to many hormones, growth factors and cytokines, which can require accelerated degradation of COX-2 via ER-associated degradation (ERAD). ERAD involves retrotranslocation of ER-resident proteins and extraction by the ATPase p97 prior to proteasomal degradation. Although diverse factors involved in retrotranslocation and ERAD have been described, degradation of many ER-resident proteins requires specific combinations of factors that have not been defined. Here (Chen et al., 2023), Song-Kun Shyue and colleagues investigate the ERAD machinery involved in COX-2 degradation and identify the ER membrane proteins derlin-1, derlin-2 and Surf4 as facilitators of COX-2 degradation upstream of p97. By carefully assessing protein–protein interactions, the authors resolve the sequential requirement of derlin-2, derlin-1, Surf4, caveolin-1 and p97 for efficient COX-2 degradation. Whereas degradation of COX-2 is dependent on its N-glycosylation state, its interaction with this ERAD machinery occurs regardless of glycosylation. Surf4, which typically regulates ER protein secretion, represents an unexpected player in this ERAD machinery. Taken together, these findings uncover a unique degradation pathway for COX-2 that might contribute to its dynamic and rapid regulation.

First scientific study on snakebites in Malawi provides important epidemiological data - BNITM

NASA Astrobiology