Open Access

ARTICLE

Gp78 regulates PMP22 and causes ER stress and autophagy in EV71-VP1-overexpressing mouse Schwann cells

by DANPING ZHU^1,#, GUANGMING LIU^1,#, KUAN FENG¹, SUYUN LI¹, DANDAN HU², SIDA YANG^3,*, PEIQING LI^1,*

1 Pediatric Emergency Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
2 Department of Child Health Care, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
3 Pediatric Neurology Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China

* Corresponding Authors: SIDA YANG. Email: ; PEIQING LI. Email:
# These authors are co-first authors and contributed equally to this work

BIOCELL 2024, 48(4), 653-664. https://doi.org/10.32604/biocell.2024.044856

Received 10 August 2023; Accepted 23 January 2024; Issue published 09 April 2024

Abstract

Background: During Enterovirus type 71 (EV71) infection, the structural viral protein 1 (VP1) activates endoplasmic reticulum (ER) stress associated with peripheral myelin protein 22 (PMP22) accumulation and induces autophagy. However, the specific mechanism behind this process remains elusive. Methods: In this research, we used the VP1-overexpressing mouse Schwann cells (SCs) models co-transfected with a PMP22 silencing or Autocrine motility factor receptor (AMFR/gp78) overexpressing vector to explore the regulation of gp78 on PMP22 and its relationship with autophagy and apoptosis. Results: The activity of gp78 could be influenced by EV71-VP1, leading to a decrease in the ubiquitination and degradation of PMP22, resulting in PMP22 accumulation in ER. In VP1-overexpressing mouse SCs, all three ER stress sensors, including pancreatic endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) and the related downstream signals (C/EBP-homologous protein (CHOP) and Caspase 12) were activated, as well as the ER-resident chaperone Glucose-regulated protein 78 (GRP78). In addition, VP1 upregulated the autophagy marker Microtubule-associated protein 1 light chain 3 beta (LC3B), while PMP22 silencing or gp78 overexpression reversed the phenomenon. Meanwhile, PMP22 silencing or gp78 overexpression increased proliferation of EV71-VP1-transfected mouse SCs. Conclusion: Gp78 could regulate PMP22 accumulation through ubiquitination degradation and cause ER stress and autophagy in EV71-VP1-overexpressing mouse SCs. Therefore, the gp78/PMP22/ER stress axis might emerge as a promising therapeutic target for myelin and neuronal damage induced by EV71 infection.

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Supplementary Material

Supplementary Material File

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