DDRGK1, a crucial player of ufmylation system, is indispensable for autophagic degradation by regulating lysosomal function.
DDRGK1, a crucial player of ufmylation system, is indispensable for autophagic degradation by regulating lysosomal function.
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DOI：
10.1038/s41419-021-03694-9
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发表时间：
2021-04-20
影响因子：
9
通讯作者：
Cai Y
中科院分区：
文献类型：
--
作者：
Cao Y;Li R;Shen M;Li C;Zou Y;Jiang Q;Liu S;Lu C;Li H;Liu H;Cai Y
含DDRGK结构域蛋白1（DDRGK 1）是新发现的泛素化系统的重要组成部分，其缺失已被报道可诱导广泛内质网（ER）应激。最近，新的证据表明ufmylation系统与自噬相关，尽管确切的机制在很大程度上仍然未知。为了探讨DDRGK 1对自噬的调控机制，本研究建立了一种从DDRGK 1F/F：ROSA 26-CreERT 2小鼠中收获的永生化小鼠胚胎成纤维细胞（MEF）系，其中DDRGK 1可被4-羟基他莫昔芬（4-OHT）处理诱导耗竭。在这里，我们发现MEFs中的DDRGK 1缺陷对自噬具有双重作用，导致自噬体的显著积累。一方面，它通过损害mTOR信号传导促进自噬诱导;另一方面，它通过抑制自噬体-溶酶体融合来阻断自噬降解。DDRGK 1耗竭对自噬的这种双重作用最终导致MEFs中的凋亡。进一步的研究表明，DDRGK 1丢失与溶酶体功能抑制相关，包括受损的组织蛋白酶D（CTSD）表达，异常的溶酶体pH值和v-ATP酶积累，这可能是自噬过程受损的潜在触发因素。因此，这项研究证实了DDRGK 1通过控制溶酶体功能作为自噬调节剂的关键作用。这可能为DDRGK 1缺陷引起的各种生理性疾病的治疗策略提供理论依据。
DDRGK domain-containing protein 1 (DDRGK1) is an important component of the newly discovered ufmylation system and its absence has been reported to induce extensive endoplasmic reticulum (ER) stress. Recently, emerging evidence indicates that the ufmylation system is correlated with autophagy, although the exact mechanism remains largely unknown. To explore the regulation mechanism of DDRGK1 on autophagy, in this study, we established an immortalized mouse embryonic fibroblast (MEF) cell lines harvested from the DDRGK1F/F:ROSA26-CreERT2 mice, in which DDRGK1 depletion can be induced by 4-hydroxytamoxifen (4-OHT) treatment. Here, we show that DDRGK1 deficiency in MEFs has a dual effect on autophagy, which leads to a significant accumulation of autophagosomes. On one hand, it promotes autophagy induction by impairing mTOR signaling; on the other hand, it blocks autophagy degradation by inhibiting autophagosome–lysosome fusion. This dual effect of DDRGK1 depletion on autophagy ultimately aggravates apoptosis in MEFs. Further studies reveal that DDRGK1 loss is correlated with suppressed lysosomal function, including impaired Cathepsin D (CTSD) expression, aberrant lysosomal pH, and v-ATPase accumulation, which might be a potential trigger for impairment in autophagy process. Hence, this study confirms a crucial role of DDRGK1 as an autophagy regulator by controlling lysosomal function. It may provide a theoretical basis for the treatment strategies of various physiological diseases caused by DDRGK1 deficiency.
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