ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy

Abstract

Highlights d ATL3 is an ER-phagy receptor and promotes tubular ER degradation d ATL3 specifically binds to GABARAP via 2 GABARAP interaction motifs (GIMs) d Sensory neuropathy-associated ATL3 mutations reduce ATL3-GABARAP binding d Sensory neuropathy-associated ATL3 mutations impair ATL3's function in ER-phagy

ER‐phagy: shaping up and destressing the endoplasmic reticulum

“…The situation with ATL3 thus parallels RTN3L, where a known ER‐reshaping factor also acts as a receptor, potentially combining ER recognition and membrane‐reshaping principles. A point mutation within the GIM of ATL3 that precludes GABARAP‐binding was found in the neuropathy HSAN type I , suggesting that dysfunctional ER‐phagy is part of the disease mechanism. Interestingly, loss‐of‐function of human ATL1 , which also participates in ER‐phagy (discussed above), underlies a related degenerative condition of the central nervous system termed hereditary spastic paraparesis (HSP) .…”

The various shades of ER‐phagy

“…ER‐phagy receptors appear to work independently from one another and primarily form homodimers/multimers. The only exception, thus far, was reported for RTN3L and ATL3, which were found to interact with one another after protein overexpression in HEK293T cells . Although the atlastins family member, ATL2, has not been officially defined as an ER‐phagy receptor, ATL2 interacts with FAM134B.…”

“…Only in recent years, after the characterization of the first ER-phagy receptors (see next paragraph), FAM134B in mammals and ATG39 and ATG40 in yeast [25,26], the molecular basis of ER-phagy was revealed and its full biological importance began to be recognized [10]. Several mammalian ER-phagy receptors have been identified so far: SEC62, RTN3 (its long isoform RTN3L), CCPG1, ATL3, and TEX264 [27][28][29][30][31][32] (Fig. 1A,B).…”

ATG8-interacting (ATI) 1 and 2 define a plant starvation-induced ER-phagy pathway and serve as MSBP1 (MAPR5) cargo-receptors

“…Atg39 localizes to the perinuclear ER, while Atg40 is enriched in the cortical and cytoplasmic ER, suggesting that each protein is needed for the degradation of a different ER subdomain [25]. In mammals, six ER-resident autophagy receptors were identified to date: FAM134B [27], the long isoform of RTN3 (RTN3L) [28], CCPG1 (cell cycle progression 1) [29], SEC62 [30], AT3 (atlastin GTPase 3) [31] and TEX264 (testis expressed gene 264) [32,33]. The different receptors seem to differ in their function and ER subdomain localization.…”

“…The different receptors seem to differ in their function and ER subdomain localization. FAM134B regulates starvation-induced turnover of ER sheets, while RTN3L and ATL3 are important for starvation-induced degradation of ER tubules [27,28,31]. CCPG1 and Sec62 are involved in ER stress induced ER-phagy [29 , 30].…”