# The role of ER associated degradation (ERAD) in hematopoietic stem cells

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $480,900

## Abstract

Abstract:
It is well established that quiescence or dormancy preserves the self-renewal and long-term reconstituting
potential of long-term HSCs (LT-HSC). HSCs that are quiescent give rise to much higher reconstitution than
proliferating HSCs in transplant recipients, and signals that drive HSCs into proliferation cycle often lead to HSC
differentiation and exhaustion. However, the mechanisms that coordinate HSC quiescence, proliferation and
differentiation remains to be investigated. Recently, we and others reported that protein homeostasis at
endoplasmic reticulum (ER) plays important role in preserving HSC functions under stressed condition. However,
it remains to be investigated whether protein quality control is important for HSCs under steady state, when the
majority of HSCs remain in a deeply dormant state with profoundly reduced protein synthesis rate and metabolic
activity. ER associated degradation (ERAD) is a critical component of protein homeostasis, and ensures protein
quality control by degrading inappropriately folded or assembled proteins in ER. ERAD complexes recognize
misfolded proteins in ER and translocate them to cytosol for proteasomal degradation. Our preliminary studies
indicate that protein quality control via ERAD governs HSC quiescence and self-renewal. The Sel1L/Hrd1 ERAD
genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic
tissues drives HSCs to hyper-proliferation, which leads to complete loss of HSC self-renewal and HSC depletion.
ERAD deficiency via Sel1L knockout induces a non-apoptotic ER stress and activates all three main pathways
of unfolded protein response (UPR). Furthermore, we found that mTOR signaling is activated in Sel1L knockout
HSCs and inhibition of mTOR via rapamycin rescues Sel1L knockout-induced HSC defects. We therefore
hypothesize that Sel1L maintains HSC quiescence and self-renewal by restricting mTORC activity. Here, we
propose three aims to determine the mechanism by which ERAD modulates mTOR signaling to preserve HSC
quiescence and self-renewal: 1) Determine the role of Akt/mTOR signaling branches in Sel1L-mediated HSC
regulation; 2) Dissect the interaction of ERAD and UPR signaling; and 3) Determine the role of Rheb in ERAD
deficiency-induced HSC dysregulation. These studies will establish Sel1L/Hrd1 ERAD as the master regulator
of HSC quiescence, and provide novel insights into how protein quality control systems coordinate with
proliferation signaling pathways to determine HSC fate.

## Key facts

- **NIH application ID:** 10850894
- **Project number:** 5R01HL150707-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Qing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $480,900
- **Award type:** 5
- **Project period:** 2020-07-03 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850894

## Citation

> US National Institutes of Health, RePORTER application 10850894, The role of ER associated degradation (ERAD) in hematopoietic stem cells (5R01HL150707-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10850894. Licensed CC0.

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