Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
Curr Biol. 2019 Mar 4;29(5):846-855.e6. doi: 10.1016/j.cub.2019.01.041. Epub 2019 Feb 14.
The endoplasmic reticulum (ER) consists of the nuclear envelope and both peripheral ER sheets and a peripheral tubular network [1, 2]. In response to physiological or pathological conditions, receptor-mediated selective ER-phagy, engulfing specific ER subdomains or components, is essential for ER turnover and homeostasis [3-6]. Four mammalian receptors for ER-phagy have been reported: FAM134B [7], reticulon 3 (RTN3) [8], SEC62 [9], and CCPG1 [10]. However, these ER-phagy receptors function in subcellular- and tissue- or physiological- and pathological-condition-specific manners, so the diversity of ER-phagy receptors and underlying mechanisms remain largely unknown [3, 4]. Atlastins (ATL1, ATL2, and ATL3), in mammals, are a class of membrane-bound, dynamin-like GTPases that function in ER fusion [11, 12]. ATL1 is expressed mainly in the central nervous system, while ATL2 and ATL3 are more ubiquitously distributed [13]. Recent studies showed that ATL2 mainly affects ER morphology by promoting ER fusion, whereas alterations in ER morphology are hardly detectable after ATL3 depletion [14, 15]. Here, we show that ATL3 functions as a receptor for ER-phagy, promoting tubular ER degradation upon starvation. ATL3 specifically binds to GABARAP, but not LC3, subfamily proteins via 2 GABARAP interaction motifs (GIMs). ATL3-GABARAP interaction is essential for ATL3 to function in ER-phagy. Moreover, hereditary sensory and autonomic neuropathy type I (HSAN I)-associated ATL3 mutations (Y192C and P338R) disrupt ATL3's association with GABARAP and impair ATL3's function in ER-phagy, suggesting that defective ER-phagy is involved in HSAN I. Therefore, we reveal a new ATL3 function for GABARAP-mediated ER-phagy in the degradation of tubular ER.
内质网（ER）由核膜和外周 ER 片层以及外周管状网络组成[1,2]。在生理或病理条件下，受体介导的选择性 ER 自噬对于 ER 周转和动态平衡至关重要，这种自噬会吞噬特定的 ER 亚域或成分[3-6]。已经报道了四种哺乳动物 ER 自噬受体：FAM134B[7]、reticulon 3 (RTN3)[8]、SEC62[9]和 CCPG1[10]。然而，这些 ER 自噬受体在亚细胞、组织或生理和病理条件下发挥作用，因此 ER 自噬受体的多样性及其潜在机制在很大程度上仍不清楚[3,4]。在哺乳动物中，atlastins (ATL1、ATL2 和 ATL3) 是一类膜结合的、类似于 dynamin 的 GTPases，它们在 ER 融合中发挥作用[11,12]。ATL1 主要在中枢神经系统中表达，而 ATL2 和 ATL3 则更为广泛分布[13]。最近的研究表明，ATL2 主要通过促进 ER 融合来影响 ER 形态，而在 ATL3 耗尽后几乎检测不到 ER 形态的改变[14,15]。在这里，我们表明 ATL3 作为 ER 自噬的受体发挥作用，在饥饿时促进管状 ER 降解。ATL3 通过 2 个 GABARAP 相互作用基序 (GIM) 特异性结合 GABARAP，但不结合 LC3 亚家族蛋白。ATL3-GABARAP 相互作用对于 ATL3 在 ER 自噬中的功能至关重要。此外，遗传性感觉和自主神经病 I 型 (HSAN I) 相关的 ATL3 突变 (Y192C 和 P338R) 破坏了 ATL3 与 GABARAP 的结合，并损害了 ATL3 在 ER 自噬中的功能，这表明 ER 自噬缺陷与 HSAN I 有关。因此，我们揭示了 ATL3 的一个新功能，即通过 GABARAP 介导的 ER 自噬来降解管状 ER。
