The integrated UPR and ERAD in oligodendrocytes maintain myelin thickness in adults by regulating myelin protein translation

Shuangchan Wu; Sarrabeth Stone; Klaus Armin Nave; Wensheng Lin

doi:10.1523/JNEUROSCI.0604-20.2020

The integrated UPR and ERAD in oligodendrocytes maintain myelin thickness in adults by regulating myelin protein translation

Shuangchan Wu, Sarrabeth Stone, Klaus Armin Nave, Wensheng Lin

Neuroscience

Research output: Contribution to journal › Article › peer-review

Abstract

Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.

Original language	English (US)
Pages (from-to)	8214-8232
Number of pages	19
Journal	Journal of Neuroscience
Volume	40
Issue number	43
DOIs	https://doi.org/10.1523/JNEUROSCI.0604-20.2020
State	Published - Oct 21 2020

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants NS094151 and NS105689 to W.L. We thank Dr. Ling Qi (University of Michigan, Ann Arbor, Michigan) for providing the Sel1LloxP/loxP mice; Dr. M. A. Aryan Namboodiri (Uniformed Services University of the Health Sciences, Bethesda, Maryland) for providing the antibody against aspartoacylase; Dr. Alexander Gow (Wayne State University, Detroit, Michigan) for providing the AA3 antibody against proteolipid protein; and Dr. Wendy Macklin (University of Colorado School of Medicine, Aurora, Colorado) for sending us the PLP KO mice. The authors declare no competing financial interests. Correspondence should be addressed to Wensheng Lin at linw@umn.edu. https://doi.org/10.1523/JNEUROSCI.0604-20.2020 Copyright © 2020 the authors

Keywords

ERAD
Myelin thickness
Oligodendrocyte
PERK
Protein translation
UPR

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

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title = "The integrated UPR and ERAD in oligodendrocytes maintain myelin thickness in adults by regulating myelin protein translation",

abstract = "Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.",

keywords = "ERAD, Myelin thickness, Oligodendrocyte, PERK, Protein translation, UPR",

author = "Shuangchan Wu and Sarrabeth Stone and Nave, {Klaus Armin} and Wensheng Lin",

note = "Funding Information: This work was supported by National Institutes of Health Grants NS094151 and NS105689 to W.L. We thank Dr. Ling Qi (University of Michigan, Ann Arbor, Michigan) for providing the Sel1LloxP/loxP mice; Dr. M. A. Aryan Namboodiri (Uniformed Services University of the Health Sciences, Bethesda, Maryland) for providing the antibody against aspartoacylase; Dr. Alexander Gow (Wayne State University, Detroit, Michigan) for providing the AA3 antibody against proteolipid protein; and Dr. Wendy Macklin (University of Colorado School of Medicine, Aurora, Colorado) for sending us the PLP KO mice. The authors declare no competing financial interests. Correspondence should be addressed to Wensheng Lin at linw@umn.edu. https://doi.org/10.1523/JNEUROSCI.0604-20.2020 Copyright {\textcopyright} 2020 the authors",

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AU - Wu, Shuangchan

AU - Stone, Sarrabeth

AU - Nave, Klaus Armin

AU - Lin, Wensheng

N1 - Funding Information: This work was supported by National Institutes of Health Grants NS094151 and NS105689 to W.L. We thank Dr. Ling Qi (University of Michigan, Ann Arbor, Michigan) for providing the Sel1LloxP/loxP mice; Dr. M. A. Aryan Namboodiri (Uniformed Services University of the Health Sciences, Bethesda, Maryland) for providing the antibody against aspartoacylase; Dr. Alexander Gow (Wayne State University, Detroit, Michigan) for providing the AA3 antibody against proteolipid protein; and Dr. Wendy Macklin (University of Colorado School of Medicine, Aurora, Colorado) for sending us the PLP KO mice. The authors declare no competing financial interests. Correspondence should be addressed to Wensheng Lin at linw@umn.edu. https://doi.org/10.1523/JNEUROSCI.0604-20.2020 Copyright © 2020 the authors

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N2 - Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.

AB - Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.

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