# Mechanisms of ER-Protein Quality Control in Podocytes

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $397,109

## Abstract

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.

## Key facts

- **NIH application ID:** 10989128
- **Project number:** 7R01DK132786-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ling Qi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,109
- **Award type:** 7
- **Project period:** 2023-11-17 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989128

## Citation

> US National Institutes of Health, RePORTER application 10989128, Mechanisms of ER-Protein Quality Control in Podocytes (7R01DK132786-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10989128. Licensed CC0.

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