Hypomorphic human SEL1L and HRD1 variants uncouple multilayered ER-associated degradation machinery
Katharine Umphred-Wilson, Stanley Adoro
Katharine Umphred-Wilson, Stanley Adoro
Published January 16, 2024
Citation Information: J Clin Invest. 2024;134(2):e175448. https://doi.org/10.1172/JCI175448.
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Hypomorphic human SEL1L and HRD1 variants uncouple multilayered ER-associated degradation machinery

Abstract

The suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) complex of the endoplasmic reticulum–associated degradation (ERAD) machinery is a key cellular proteostasis pathway. Although previous studies have shown ERAD as promoting the development and maintenance of many cell types in mice, its importance to human physiology remained undetermined. In two articles in this issue of the JCI, Qi and colleagues describe four biallelic hypomorphic SEL1L and HRD1 variants that were associated with neurodevelopment disorders, locomotor dysfunction, impaired immunity, and premature death in patients. These pathogenic SEL1L-HRD1 variants shine a light on the critical importance of ERAD in humans and pave the way for future studies dissecting ERAD mechanisms in specific cell types.

Authors

Katharine Umphred-Wilson, Stanley Adoro

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Figure 1

Human SEL1L and HRD1 variants disrupt ERAD and cause disease.

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Human SEL1L and HRD1 variants disrupt ERAD and cause disease. In normal ...
In normal cells, misfolded proteins in the ER are bound by the molecular chaperones ERLEC1 and OS9, both of which bring them to the SEL1L-HRD1 complex for ubiquitination and degradation to maintain cellular proteostasis. Qi and colleagues (11, 12) describe missense mutations in SEL1L and HRD1 that encode SEL1L-HRD1 variants with hypomorphic activity in ERAD and were associated with a spectrum of developmental disorders termed ENDI and ENDI-A. These SEL1L and HRD1 variants appear to disrupt ERAD function by impairing either enzymatic activity (HRD1 p.P398L), protein stability (SEL1L p.M528R and p.C141Y), or interactions with other ERAD components (SEL1L p.G585D).