1. Academic Validation
  2. Ubiquitination of ALOX15 regulates endoplasmic reticulum stress in Schwann cells and experimental autoimmune neuritis (EAN) models

Ubiquitination of ALOX15 regulates endoplasmic reticulum stress in Schwann cells and experimental autoimmune neuritis (EAN) models

  • Free Radic Biol Med. 2025 Jul:234:141-150. doi: 10.1016/j.freeradbiomed.2025.04.018.
Jihe Song 1 Baichao Han 1 Xinshu Du 1 Hongping Chen 1 Meng Li 1 Zhanbin Tang 1 Chen Xu 1 Wan Wei 1 Feihong Jia 1 Xinrui Wang 1 Shuanghong Sun 1 Di Zhong 2
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 2 Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: sjnkzhongdi@163.com.
Abstract

In the pathogenesis of experimental autoimmune neuritis (EAN), Schwann cells execute critical myelination functions through their characteristic axonal ensheathment, thereby facilitating saltatory conduction via myelin sheath formation. Our investigations reveal that arachidonate 15-lipoxygenase (ALOX15) modulates endoplasmic reticulum (ER) stress dynamics in both in vitro Schwann cell cultures and in vivo EAN models. Genetic silencing of ALOX15 significantly attenuated clathrin-mediated ER stress activation in Schwann cells, with mechanistic studies implicating 15-hydroxyeicosatetraenoic acid (15-HETE), the principal catalytic metabolite of ALOX15, as a key mediator of ER stress potentiation. Notably, we identified a self-reinforcing oxidative stress circuit involving mitochondrial-ER crosstalk, characterized by mitochondrial calcium overload and subsequent activation of the mitochondrial permeability transition pore (mPTP). This pathological interplay was corroborated by elevated expression of ER stress markers and increased Reactive Oxygen Species (ROS) production in EAN neural tissues. Through integrated mass spectrometry analysis and molecular validation, we established RBX1 (RING-box protein 1) as the cognate E3 ubiquitin Ligase responsible for ALOX15 regulation in rat models. The observed upregulation of RBX1 expression in EAN-affected Schwann cells suggests a novel regulatory mechanism for ALOX15 protein homeostasis. In summary, the present study offers novel insights into the mechanism by which ALOX15 regulates ER stress in Schwann cells and the EAN model.

Keywords

EAN model; Endoplasmic reticulum stress; Reactive oxygen species; Schwann cells; Ubiquitination.

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