Study On Biological Function Of FAM134B Oligomerization In ER-phagy

The endoplasmic reticulum(ER)is the largest intracellular organelle,which constitutes a continuous intracellular network of sheet and tubular membrane structures.ER plays essential roles in protein and lipid synthesis,calciun homeostasis,organelle communications and innate immunity.The oscillation of ER size and shape in response to varying environmental cues is crucial to cell homeostasis.Redundant ER can be degraded as a cargo of selective autophagy pathway,which is coined as ER-phagy.Selective autophagy is a cellular quality control pathway through which a variety of autophagy cargoes are specifically engulfed by autophagosomes and delivered to lysosomes for degradation.The specificity of this process is governed by autophagy receptors that simultaneously bind to cargoes and the LC3 family members on the expanding autophagosomal membranes.Recent studies have greatly advanced the understanding of ER-phagy by identifying the key autophagy receptors FAM134B,RTN3L,SEC62,CCPGI,ATL3,Atg39 and Atg40.One essential question remains unsolved is that how ER membrane is fragmented into "bite size,for subsequent autophagosomal sequestration.Moreover,little is known about how environmental or intracellular signals are transduced to trigger ER-phagy in a time-dependent manner.Lastly,the cause and consequence of excessive ER-phagy are poorly understood.FAM134B-mediated ER-phagy appears to be a good model system to address above questions,because FAM134B induces liposome fragmentation in vitro and mediates ER-phagy in vivo,and more importantly,the dysfunction of FAM134B causes hereditary sensory and autonomic neuropathy type 2(HSAN Ⅱ).In this study,we show that FAM134B oligomerization drives the fragmentation of ER prior to ER-phagy.Next,ER stress triggers CAMK2B-mediated FAM134B phosphorylation,which further enhances FAM134B oligomerization,ER scission and ER-phagy.To strengthen our model,we provide evidence that a type Ⅱ HSAN patient-derived FAM134B variant,FAM134BGZ16R appears to be a gain-of-function mutant,as it is hyperactive in oligomerization,ER fragmentation and ER-phagy,which results in sensory neuron death.Therefore,this study not only identifies a regulatory mechanism in ER membrane scission,but also reveales that excessive selective autophagy may cause human diseases.