# Defining the Central Role of ER-Associated Degradation (ERAD) in Neuroendocrine Cells

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $405,107

## Abstract

Defining the Central Role of ER-Associated Degradation (ERAD) in Neuroendocrine Cells
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. Failure to clear misfolded proteins
in the ER presumably activates the unfolded protein response, or UPR. We showed that Sel1L-Hrd1 ERAD
modulates the activation of UPR sensor IRE1a by mediating its turnover (Sun et al. 2015 Nat Cell Biol). In two
recent studies, we reported that impaired ERAD function may be directly linked to the pathogenesis of metabolic
diseases, thereby holding significant therapeutic potential (Shi et al. 2017 and Kim et al. 2018 J CIin Invest).
Specifically, we reported that mice with Sel1L deficiency in either AVP or POMC neurons exhibit diabetes
insipidus and early-onset obesity, respectively. We showed that Sel1L-Hrd1 ERAD controls the maturation of
two prohormones, proAVP and POMC, within the ER by targeting the misfolded forms for proteasomal
degradation, thereby preventing the aggregation of a large proportion of native prohormones. We now propose
to test the overarching hypothesis that the Sel1L-Hrd1 ERAD protein complex plays a critical role in
neuroendocrine cells by directly recruiting misfolded prohormones for proteasomal degradation and by
coordinating the activation of other ER quality-control machineries, such as UPR and autophagy, to ensure
proper prohormone maturation and neuronal homeostasis. This model challenges the current paradigm in ER
biology by placing ERAD at the center of cellular function in normal physiology and disease pathogenesis. Using
POMC neurons as a model system, we will accomplish the following Aims: (1) determine the underlying
molecular mechanisms and therapeutic potential of ERAD-POMC interactions; (2) demonstrate the
pathophysiological importance and mechanisms underlying the crosstalk between ERAD and autophagy in
POMC neurons; and (3) demonstrate the pathophysiological importance and mechanisms underlying the
crosstalk between ERAD and IRE1α in POMC neurons. This study will provide unprecedented insights into
ERAD function and prohormone biology in neuroendocrine cells, which has direct clinical implications for human
diseases that are associated with defects of prohormone folding and export.
RELEVANCE TO HUMAN HEALTH: All neuropeptides are synthesized as precursor proteins known as
“prohormones” in the ER; however, molecular mechanisms underlying their maturation within the ER remain
poorly understood. This study will establish the pathophysiological significance of ERAD in coordinating ER
homeostasis during prohormone maturation and explore the therapeutic potential of targeting ERAD in th...

## Key facts

- **NIH application ID:** 9979646
- **Project number:** 5R01DK120047-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ling Qi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,107
- **Award type:** 5
- **Project period:** 2018-09-22 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979646

## Citation

> US National Institutes of Health, RePORTER application 9979646, Defining the Central Role of ER-Associated Degradation (ERAD) in Neuroendocrine Cells (5R01DK120047-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9979646. Licensed CC0.

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