Hhatl ameliorates endoplasmic reticulum stress through autophagy by associating with LC3

Xingjuan Shi; Jiayu Yao; Yexi Huang; Yushan Wang; Xuan Jiang; Ziwen Wang; Mingming Zhang; Yu Zhang; Xiangdong Liu

doi:10.1016/j.jbc.2024.107335

Hhatl ameliorates endoplasmic reticulum stress through autophagy by associating with LC3

J Biol Chem. 2024 May 3:107335. doi: 10.1016/j.jbc.2024.107335. Online ahead of print.

Authors

Xingjuan Shi¹, Jiayu Yao², Yexi Huang², Yushan Wang², Xuan Jiang², Ziwen Wang², Mingming Zhang², Yu Zhang², Xiangdong Liu²

Affiliations

¹ School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China. Electronic address: xingjuanshi@seu.edu.cn.
² School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China.

PMID: 38705394
DOI: 10.1016/j.jbc.2024.107335

Abstract

Endoplasmic reticulum (ER) stress, a common cellular stress response induced by various factors that interfere with cellular homeostasis, may trigger cell apoptosis. Autophagy is an important and conserved mechanism for eliminating aggregated proteins and maintaining protein stability of cells, which is closely associated with ER stress and ER stress-induced apoptosis. In this paper, we report for the first time that Hhatl, an ER-resident protein, is downregulated in response to ER stress. Hhatl overexpression alleviated ER stress and ER stress induced apoptosis in cells treated with tunicamycin or thapsigargin, whereas Hhatl knockdown exacerbated ER stress and apoptosis. Further study showed that Hhatl attenuates ER stress by promoting autophagic flux. Mechanistically, we found that Hhatl promotes autophagy by associating with autophagic protein LC3 (microtubule-associated protein 1A/1B-light chain 3) via the conserved LC3-interacting region (LIR) motif. Noticeably, the LIR motif was essential for Hhatl-regulated promotion of autophagy and reduction of ER stress. These findings demonstrate that Hhatl ameliorates ER stress via autophagy activation by interacting with LC3, thereby alleviating cellular pressure. The study indicates that pharmacological or genetic regulation of Hhatl-autophagy signaling might be potential for mediating ER stress and related diseases.

Keywords: ER stress; Hhatl; LC3; autophagy.