The integrated unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) is the principle mechanisms that maintain endoplasmic reticulum (ER) homeostasis. Schwann cells (SCs) must produce an enormous amount of myelin proteins via the ER to assemble and maintain myelin structure; however, it is unclear how SCs maintain ER homeostasis. It is known that Suppressor/Enhancer of Lin-12-like (Sel1L) is necessary for the ERAD activity of the Sel1L- hydroxymethylglutaryl reductase degradation protein 1(Hrd1) complex. Herein, we showed that Sel1L deficiency in SCs impaired the ERAD activity of the Sel1L-Hrd1 complex and led to ER stress and activation of the UPR. Interestingly, Sel1L deficiency had no effect on actively myelinating SCs during development, but led to later-onset mature SC apoptosis and demyelination in the adult PNS. Moreover, inactivation of the pancreatic ER kinase (PERK) branch of the UPR did not influence the viability and function of actively myelinating SCs, but resulted in exacerbation of ER stress and apoptosis of mature SCs in SC-specific Sel1L deficient mice. These findings suggest that the integrated UPR and ERAD is dispensable to actively myelinating SCs during development, but is necessary for maintaining ER homeostasis and the viability and function of mature SCs in adults.
Bibliographical noteFunding Information:
We thank Dr. Ling Qi (University of Michigan, Ann Arbor, Michigan) for providing the mice. We thank Dr. Klaus‐Armin Nave (Max Planck Institute of Experimental Medicine, Göttingen, Germany) for providing the CNP/Cre mice. This study was supported by grants from the National Institutes of Health (NS094151 and NS105689) to W. L. Sel1L loxP/loxP
We thank Dr. Ling Qi (University of Michigan, Ann Arbor, Michigan) for providing the Sel1LloxP/loxP mice. We thank Dr. Klaus-Armin Nave (Max Planck Institute of Experimental Medicine, G?ttingen, Germany) for providing the CNP/Cre mice. This study was supported by grants from the National Institutes of Health (NS094151 and NS105689) to W. L.
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- Schwann cells