登革病毒 (DENV) 屬於黃病毒科中的黃病毒屬。DENV非結構蛋白1 (NS1) 是一種會從DENV感染的細胞中分泌出去的病毒蛋白。血清中高水平的NS1被發現與患者的嚴重臨床疾病息息相關。然而，目前NS1分泌的潛在機制尚未完全清楚。在我們的初步數據中，我們發現NS1能夠通過自噬相關的非傳統途徑分泌。此外，Rab37是一種參與自噬體形成的GTPase蛋白，並且會參與NS1的分泌。在這項研究中，我們進一步研究了Rab37如何通過自噬相關的非傳統途徑調節NS1的分泌。根據我們的結果，我們發現敲除Rab37後，在DENV感染的A549細胞中病毒複製以及NS1的分泌都減少了。再者，在缺乏Rab37的細胞中LC3-II的轉換和螢光點均下調，這表示Rab37可能調節DENV誘導的自噬。除此之外，我們發現 NS1是個被Rab37囊泡所包裹的一種貨物蛋白，並且會透過帶有GTP的Rab37囊泡運輸將NS1分泌出去。另一方面，目前已知NS1的醣基化也會影響NS1的分泌。而NS1 殘基有兩個重要的醣基化位點，Asn(N)-130和Asn(N)-207。我們生成了兩個穩定表達突變體NS1N130Q或NS1N207Q的A549細胞株。與對照組細胞相比，在表達NS1N130Q或NS1N207Q的細胞中，不僅DENV NS1的分泌顯著減少，而且NS1、LC3和Rab37的三重共定位也顯著減少。總而言之，NS1上N-130和N-207位點的醣基化對於Rab37和NS1分泌的自噬至關重要。這些結果強調出了Rab37在調節DENV NS1分泌中的貢獻。

Dengue virus (DENV) belongs to the genus Flavivirus of the family Flaviviridae. DENV non-structural protein 1 (NS1) is the only viral protein secreted from DENV-infected cells. High serum levels of NS1 are found to associate with severe clinical disease in patients. However, the underlying mechanisms of NS1 secretion are not fully understood. In our preliminary data, we showed that NS1 can be secreted through the autophagy-associated unconventional pathway. Moreover, Rab37, a GTPase protein participating in the formation of autophagosome, was involved in the secretion of NS1. In this study, we investigated how Rab37 regulates the secretion of NS1 through an autophagy-associated unconventional pathway. As from our results, we found that knockdown of Rab37 reduced virus replication as well as NS1 secretion in DENV-infected A549 cells. In addition, the LC3- II conversion and punctation were both down-regulated in Rab37 silencing cells, suggesting that Rab37 may regulate DENV-induced autophagy. Furthermore, we found that NS1 serves as a cargo protein of Rab37-coated vesicles and is secreted via Rab37 GTP-dependent vesicle trafficking. On the other hand, it has been revealed that glycosylation of NS1 affects NS1 secretion. There are two important N-linked glycosylation sites at NS1 residues, Asn(N)-130 and Asn(N)-207. We have generated two A549 cells that are stably expressing mutant NS1N130Q or NS1N207Q. Compared to wild-type control cells, the secretion of DENV NS1 and the triple colocalization of NS1, LC3, and Rab37 were significantly reduced in NS1N130Q or NS1N207Q expressing cells. In conclusion, these results indicate that glycosylation at N-130 and N-207 sites on NS1 is essential to be targeted by Rab37 and autophagy for NS1 secretion. These results highlight the contribution of Rab37 in the regulation of DENV NS1 secretion.

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