Abstract
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a quality control system that induces the degradation of ER terminally misfolded proteins. The ERAD system consists of complexes of multiple ER membrane-associated and luminal proteins that function cooperatively. We aimed to reveal the role of Derlin-3 in the ERAD system using the liver, pancreas, and kidney obtained from different mouse genotypes. We performed coimmunoprecipitation and sucrose density gradient centrifugation to unravel the dynamic nature of ERAD complexes. We observed that Derlin-3 is exclusively expressed in the pancreas, and its deficiency leads to the destabilization of Herp and accumulation of ERAD substrates. Under normal conditions, Complex-1a predominantly contains Herp, Derlin-2, HRD1, and SEL1L, and under ER stress, Complex-1b contains Herp, Derlin-3 (instead of Derlin-2), HRD1, and SEL1L. Complex-2 is upregulated under ER stress and contains Derlin-1, Derlin-2, p97, and VIMP. Derlin-3 deficiency suppresses the transition of Derlin-2 from Complex-1a to Complex-2 under ER stress. In the pancreas, Derlin-3 deficiency blocks Derlin-2 transition. In conclusion, the composition of ERAD complexes is tissue-specific and changes in response to ER stress in a Derlin-3-dependent manner. Derlin-3 may play a key role in changing ERAD complex compositions to overcome ER stress.
Highlights
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) can result in a cellular condition called ER stress
We developed Herp-deficient mice, which exhibit a vulnerability to ER stress and defects in the degradation of ER-associated protein degradation (ERAD) substrates in the liver [29]
We reveal that at least three types of ERAD complexes exist, and their compositions differ in response to ER stress in a Derlin-3-dependent manner
Summary
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) can result in a cellular condition called ER stress. ER stress is associated with various diseases, such as neurodegenerative diseases, metabolic diseases, inflammatory diseases, and cancer [1]. To overcome this stress, the cell upregulates a variety of proteins transcriptionally and translationally [2,3]. The cell upregulates a variety of proteins transcriptionally and translationally [2,3] Some of these are involved in a specialized protein disposal system called ER-associated protein degradation (ERAD). The process begins with the recognition of ERAD substrates, which are transported to the cytosol, ubiquitinated, and degraded by the proteasome [4,5,6]
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