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SEL1L–HRD1-mediated ERAD in mammals

Nature Cell Biology volume 27, pages 1063–1073 (2025)Cite this article

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Abstract

Endoplasmic reticulum-associated degradation (ERAD) is a critical quality control mechanism responsible for eliminating misfolded or unassembled proteins. It maintains endoplasmic reticulum homeostasis, ensures a proper folding environment and regulates substrate protein levels. Following its discovery in the late 1980s and early 1990s, research on ERAD in mammals—particularly that mediated by the conserved protein complex comprising suppressor/enhancer of Lin-12-like protein 1-like (SEL1L) and HMG-CoA reductase degradation protein 1 (HRD1)—has advanced substantially over the past decade. SEL1L–HRD1-mediated ERAD is now recognized as a fundamental process in mammals that governs various physiological functions largely in a substrate-specific manner. In humans, mutations in this complex have been causally linked to ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) and ENDI-agammaglobulinaemia. This Review highlights the SEL1L–HRD1-mediated ERAD pathway, exploring its machinery, molecular mechanism and physiological relevance and potential therapeutic strategies targeting this system.

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Fig. 1: ER quality control pathways.
Fig. 2: The SEL1L–HRD1 ERAD pathway: core components, cofactors, structural insights and representative endogenous substrates.
Fig. 3: Proposed autoregulatory feedback loop of the SEL1L–HRD1 ERAD complex.
Fig. 4: Pathogenic SEL1L and HRD1 variants in humans.

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Acknowledgements

We apologize to colleagues whose works were not cited due to space limitations. This work was supported by R01DK128077 and R01DK132068 (to S.S); the Alzheimer’s Association (24AARG-D-NTF-1187603), 1R01AG089640, 1R01DK120330, 1R01DK137794, 1R01DK132786, 1R01DK111174 and 1R35GM130292 (to L.Q.); and 1R01NS138119 (to S.S. and L.Q.). H.H.W. is supported by an Alzheimer’s Association Postdoctoral Research Fellowship (25AARF-1375486).

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Authors and Affiliations

  1. Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA

    Huilun Helen Wang & Ling Qi

  2. Department of Translational Medicine, University of Pavia, Pavia, Italy

    Ida Biunno

  3. Integrated Systems Engineering, Brugherio, Italy

    Ida Biunno

  4. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA

    Shengyi Sun

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  1. Huilun Helen Wang
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  2. Ida Biunno
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  3. Shengyi Sun
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Contributions

H.H.W., S.S. and L.Q. conceptualized the manuscript and co-wrote the majority of the text. H.H.W. generated the figures. I.B. contributed to the writing of Box 1. I.B. and S.S. provided critical edits. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Shengyi Sun or Ling Qi.

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Wang, H.H., Biunno, I., Sun, S. et al. SEL1L–HRD1-mediated ERAD in mammals. Nat Cell Biol 27, 1063–1073 (2025). https://doi.org/10.1038/s41556-025-01690-1

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