Tuesday, February 4, 2025
2/4/2025
Mechanisms of ER Protein Quality Control in Podocytes SUMMARY My laboratory has a long-standing interest in protein folding and degradation within the endoplasmic reticulum (ER) by defining the physiological and pathological importance of mammalian ER quality-control machineries in vivo. ER-associated degradation (ERAD) is the principal protein quality-control mechanism responsible for targeting misfolded proteins in the ER for cytosolic proteasomal degradation. The SEL1L-HRD1 protein complex represents the most conserved branch of ERAD. We recently showed that mice with Sel1L deficiency in podocytes develop proteinuria at ~5 weeks of age and die prematurely with a median life span of ~14 weeks for both males and females (Yoshida et al. 2021 J CIin Invest). Electron microscopic analyses revealed foot process effacement and impaired slit diaphragm in the absence of Sel1L. Mechanistically, we showed that SEL1L-HRD1 ERAD in podocytes plays a critical role in the maturation of nascent nephrin in the ER, without affecting podocyte cell number and survival. In our recent work, our preliminary data suggested a possible crosstalk, or likely synergism, between ERAD and another key degradative pathway autophagy in podocytes. We propose to test the overarching hypothesis that the SEL1L-HRD1 ERAD protein complex plays a critical role in podocytes by coordinating the activation of autophagy, which ensures cellular homeostasis and filtration function. This model challenges/expands the current paradigm in ER biology by placing SEL1L-HRD1 ERAD at the center of cellular function in normal physiology and disease pathogenesis. Using various mouse models, we will accomplish the following Aims: (1) Demonstrate the pathophysiological importance of the crosstalk between SEL1L-HRD1 ERAD and autophagy in podocytes; (2) Determine how SEL1L-HRD1 ERAD controls autophagy activity in podocytes; and (3) Delineate the pathological importance and mechanism of ERAD and autophagy in the pathogenesis of nephrin disease mutants involved in nephrotic syndrome. This study will provide unprecedented insights into the crosstalk among key ER quality control machineries in podocytes, and shed new light on the therapeutic potential of targeting ER homeostasis in podocytes. RELEVANCE TO HUMAN HEALTH: Defects in podocytes and in the formation slit diaphragm, a specialized structure involving many transmembrane proteins, underlie nephrotic syndrome, affecting children and adults of all ages. While the ER quality control systems are presumably integrated to maintain ER homeostasis, the crosstalk between quality-control systems has not yet been investigated in vivo. This study will establish the pathophysiological significance of ERAD and the crosstalk between ERAD and autophagy in podocytes in health and diseases.
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