N-glycan processing selects ERAD-resistant misfolded proteins for ER-to-lysosome-associated degradation.
N-glycan processing selects ERAD-resistant misfolded proteins for ER-to-lysosome-associated degradation.
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DOI：
10.15252/embj.2020107240
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发表时间：
2021-08-02
期刊：
影响因子：
--
通讯作者：
Molinari M
中科院分区：
文献类型：
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作者：
Fregno I;Fasana E;Soldà T;Galli C;Molinari M
蛋白质生物合成副产物的有效降解维持细胞适应性。引人注目的是，真核细胞中主要的生物合成区室，内质网（ER），缺乏降解机制。ER中错误折叠的蛋白质通过ER相关降解（ERAD）转移到细胞溶质中进行蛋白酶体降解。或者，它们在ER亚结构域中分离，这些亚结构域从生物合成区室脱落，并在ER吞噬受体的控制下递送至内溶酶体，以进行ER至溶酶体相关降解（ERLAD）。N-连接寡糖的去糖基化作用靶向ERAD的末端错误折叠蛋白。错误折叠的蛋白质最终如何标记为ERLAD尚不清楚。在这里，我们表明对于ATZ和突变型前胶原，所选N-聚糖的去葡萄糖基化/再葡萄糖基化循环以及与钙连接蛋白（CNX）的持续缔合是必需的，并且足以标记FAM 134 B驱动的溶酶体递送的ERAD抗性错误折叠蛋白。总之，我们表明N-聚糖的甘露糖和葡萄糖加工是触发事件，分别将ER中的错误折叠蛋白靶向蛋白酶体（ERAD）和溶酶体（ERLAD）清除，调节真核细胞中的蛋白质质量控制。N-聚糖去葡萄糖基化/葡萄糖基化循环和与Calnexin的持续结合靶向哺乳动物细胞中的α1-抗胰蛋白酶-Z聚合物和错误折叠的前胶原至ERLAD。
Efficient degradation of by‐products of protein biogenesis maintains cellular fitness. Strikingly, the major biosynthetic compartment in eukaryotic cells, the endoplasmic reticulum (ER), lacks degradative machineries. Misfolded proteins in the ER are translocated to the cytosol for proteasomal degradation via ER‐associated degradation (ERAD). Alternatively, they are segregated in ER subdomains that are shed from the biosynthetic compartment and are delivered to endolysosomes under control of ER‐phagy receptors for ER‐to‐lysosome‐associated degradation (ERLAD). Demannosylation of N‐linked oligosaccharides targets terminally misfolded proteins for ERAD. How misfolded proteins are eventually marked for ERLAD is not known. Here, we show for ATZ and mutant Pro‐collagen that cycles of de‐/re‐glucosylation of selected N‐glycans and persistent association with Calnexin (CNX) are required and sufficient to mark ERAD‐resistant misfolded proteins for FAM134B‐driven lysosomal delivery. In summary, we show that mannose and glucose processing of N‐glycans are triggering events that target misfolded proteins in the ER to proteasomal (ERAD) and lysosomal (ERLAD) clearance, respectively, regulating protein quality control in eukaryotic cells. Cycles of N‐glycan deglucosylation/glucosylation and persistent binding to Calnexin target α1‐antitrypsin‐Z polymers and misfolded pro‐collagen to ERLAD in mammalian cells.