<br>SLC3A2 N-糖基化和高尔基体重塑调节 SLC7A 氨基酸交换和应激缓解,Journal of Biological Chemistry

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SLC3A2 N-糖基化和高尔基体重塑调节 SLC7A 氨基酸交换和应激缓解
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2023-11-02 , DOI: 10.1016/j.jbc.2023.105416
Cunjie Zhang ₁ , Massiullah Shafaq-Zadah ₂ , Judy Pawling ₁ , Geoffrey G Hesketh ₁ , Estelle Dransart ₂ , Karina Pacholczyk ₁ , Joseph Longo ₃ , Anne-Claude Gingras ₄ , Linda Z Penn ₃ , Ludger Johannes ₂ , James W Dennis ₅

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蛋白质稳态需要氧化代谢（ATP）和减轻谷胱甘肽造成的相关损伤，而随着衰老的关系日益失调。 SLC3A2 (4F2hc, CD98) 作为 SLC7A5 和 SLC7A11 交换器的二硫键连接接头发挥作用，分别输入必需氨基酸和胱氨酸，同时输出 Gln 和 Glu。 SLC3A2 上 N-糖基化位点的位置随着灵长类动物的出现而进化，大概与新陈代谢同步。在此，我们报告 SLC3A2 的四个位点中的每一个都具有不同的高尔基体修饰 N-聚糖特征。灵长类衍生位点 N381 处的 N-聚糖稳定了半乳糖凝集素 3 晶格中的 SLC3A2，以抵抗包被凹坑内吞作用，而最接近膜的位点 N365 则促进糖脂半乳糖凝集素 3 (GL-Lect) 驱动的内吞作用。我们的结果表明，表面保留和内吞作用通过 SLC3A2 上 N-聚糖的数量、位置和重塑精确平衡。此外，蛋白质组学和功能分析揭示了 SLC3A2*SLC7A5 异二聚体与氨基酸/Na 同向转运体（SLC1A4、SLC1A5）的 N-聚糖依赖性聚类，平衡支链氨基酸和 Gln 水平，但以 ATP 为代价来维持Na/K 梯度。在充足的条件下，SLC3A2 相互作用需要 N365D 和 N381D 处的高尔基体修饰的 N-聚糖，而通过氟伐他汀治疗减少内质网中的 N-糖基化促进了缓解应激所需的 CD44 和转运蛋白的募集。因此，SLC3A2 N-糖基化和 N-聚糖的高尔基体重塑在生长、维持和代谢应激的氨基酸输入中具有独特的作用。

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SLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigation

Proteostasis requires oxidative metabolism (ATP) and mitigation of the associated damage by glutathione, in an increasingly dysfunctional relationship with aging. SLC3A2 (4F2hc, CD98) plays a role as a disulfide-linked adaptor to the SLC7A5 and SLC7A11 exchangers which import essential amino acids and cystine while exporting Gln and Glu, respectively. The positions of N-glycosylation sites on SLC3A2 have evolved with the emergence of primates, presumably in synchrony with metabolism. Herein, we report that each of the four sites in SLC3A2 has distinct profiles of Golgi-modified N-glycans. N-glycans at the primate-derived site N381 stabilized SLC3A2 in the galectin-3 lattice against coated-pit endocytosis, while N365, the site nearest the membrane promoted glycolipid-galectin-3 (GL-Lect)-driven endocytosis. Our results indicate that surface retention and endocytosis are precisely balanced by the number, position, and remodeling of N-glycans on SLC3A2. Furthermore, proteomics and functional assays revealed an N-glycan-dependent clustering of the SLC3A2∗SLC7A5 heterodimer with amino-acid/Na symporters (SLC1A4, SLC1A5) that balances branched-chain amino acids and Gln levels, at the expense of ATP to maintain the Na/K gradient. In replete conditions, SLC3A2 interactions require Golgi-modified N-glycans at N365D and N381D, whereas reducing N-glycosylation in the endoplasmic reticulum by fluvastatin treatment promoted the recruitment of CD44 and transporters needed to mitigate stress. Thus, SLC3A2 N-glycosylation and Golgi remodeling of the N-glycans have distinct roles in amino acids import for growth, maintenance, and metabolic stresses.

更新日期：2023-11-02

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