ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy
ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy
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ATL3 是 GABARAP 介导的选择性自噬的管状 ER 自噬受体
DOI：
10.1016/j.cub.2019.01.041
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发表时间：
2019-03-04
期刊：
影响因子：
9.2
通讯作者：
Chen, Jianguo
中科院分区：
文献类型：
--
作者：
Chen, Qingzhou;Xiao, Ya;Chen, Jianguo
内质网 (ER) 由核膜、外周 ER 表和外周管状网络组成 [1, 2]。为了响应生理或病理条件，受体介导的选择性 ER 吞噬，吞噬特定的 ER 子结构域或成分，对于 ER 更新和稳态至关重要 [3-6]。已报道 ER 吞噬的四种哺乳动物受体：FAM134B [7]、reticulon 3 (RTN3) [8]、SEC62 [9] 和 CCPG1 [10]。然而，这些 ER 吞噬受体以亚细胞和组织或生理和病理条件特异性方式发挥作用，因此 ER 吞噬受体的多样性和潜在机制仍然很大程度上未知 [3, 4]。哺乳动物中的 Atlastin（ATL1、ATL2 和 ATL3）是一类膜结合、动力样 GTP 酶，在内质网融合中发挥作用 [11, 12]。 ATL1主要表达于中枢神经系统，而ATL2和ATL3分布更为普遍[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 ATL3 耗尽后很难检测到 ER 形态的变化 [14, 15]。在这里，我们证明 ATL3 作为 ER 吞噬的受体发挥作用，在饥饿时促进肾小管 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 在内质网吞噬中发挥作用至关重要。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的关联，并损害了ATL3在ER自噬中的功能，表明HSAN I中涉及有缺陷的ER自噬。因此，我们揭示了ATL3在管状ER降解中GABARAP介导的ER自噬的新功能。
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.