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FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.


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.

SUBMITTER: Jiang X 

PROVIDER: S-EPMC7049798 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.

Jiang Xiao X   Wang Xinyi X   Ding Xianming X   Du Mengjie M   Li Boran B   Weng Xialian X   Zhang Jingzi J   Li Lin L   Tian Rui R   Zhu Qi Q   Chen She S   Wang Liang L   Liu Wei W   Fang Lei L   Neculai Dante D   Sun Qiming Q  

The EMBO journal 20200113 5


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, activa  ...[more]

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