2. Academic Validation
  3. FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy

FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy

  • EMBO J. 2020 Mar 2;39(5):e102608. doi: 10.15252/embj.2019102608.
Xiao Jiang # 1,  Xinyi Wang # 1,  Xianming Ding # 1,  Mengjie Du 2,  Boran Li 1,  Xialian Weng 3,  Jingzi Zhang 4,  Lin Li 5,  Rui Tian 1,  Qi Zhu 1,  She Chen 5,  Liang Wang 2,  Wei Liu 1,  Lei Fang 4,  Dante Neculai 3,  Qiming Sun 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Department of Neurology of Second Affiliated Hospital, Institute of Neuroscience, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Cell Biology, Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
  • 5 National Institute of Biological Sciences, Beijing, China.
  • # Contributed equally.
PMID: 31930741 DOI: 10.15252/embj.2019102608
Abstract

Degradation of endoplasmic reticulum (ER) by selective Autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain-of-function defects, such as hyperactive self-association and membrane scission, which results in excessive ER-phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective Autophagy in human diseases.

Keywords

CAMK2B; ER stress; ER-phagy; FAM134B oligomerization; membrane fragmentation.

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