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SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex
Liangguang Leo Lin1, Huilun Helen Wang1, Brent Pederson2
1Department of Molecular Physiology and Biological Physics, University of Virginia, School of Medicine, Charlottesville, VA, 22903, USA.
Nature Communications
|February 16, 2024
Summary
A pathogenic SEL1L mutation causes partial embryonic lethality and ataxia in mice by disrupting the ERAD complex. This highlights SEL1L
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- The SEL1L-HRD1 complex is a conserved pathway for endoplasmic reticulum (ER)-associated degradation (ERAD).
- In vivo evidence for SEL1L's role in ERAD complex formation and its physiological relevance in mammals is limited.
Purpose of the Study:
- To investigate the in vivo function of the SEL1L-HRD1 complex in mammals.
- To elucidate the molecular mechanisms underlying SEL1L-mediated ERAD complex formation and its link to disease.
Main Methods:
- Generation and analysis of mice carrying a pathogenic SEL1L variant (p.Ser658Pro).
- Biochemical assays to assess protein stability and protein-protein interactions.
- Proteomic analysis to identify SEL1L and HRD1 interactomes.
Main Results:
- The SEL1LS658P variant causes partial embryonic lethality, developmental delay, and cerebellar ataxia in mice.
- The variant reduces SEL1L protein stability and attenuates SEL1L-HRD1 interaction.
- SEL1L is essential for recruiting UBE2J1 and DERLIN to HRD1, forming a functional HRD1 ERAD complex.
Conclusions:
- The SEL1L-HRD1 ERAD pathway is crucial for mammalian development and neurological function.
- SEL1L is indispensable for the assembly of a functional HRD1 ERAD complex.
- SEL1L-HRD1 ERAD dysfunction is linked to neurological disorders.
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