Kaposi’s sarcoma-associated herpesvirus ubiquitin ligases downregulate cell surface expression of l-selectin
Kaposi’s sarcoma-associated herpesvirus ubiquitin ligases downregulate cell surface expression of l-selectin
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卡波西肉瘤相关疱疹病毒泛素连接酶下调细胞表面 L-选择素的表达
DOI：
10.1099/jgv.0.001678
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发表时间：
2021
影响因子：
3.8
通讯作者：
Kanamoto Taisei
中科院分区：
文献类型：
--
作者：
Kajikawa Mizuho;Imaizumi Nanae;Machii Shiho;Nakamura Tomoka;Harigane Nana;Kimura Minako;Miyano Kei;Ishido Satoshi;Kanamoto Taisei
卡波西肉瘤相关疱疹病毒（KSHV）是免疫功能低下患者卡波西肉瘤和原发性渗出性淋巴瘤的致癌病因。KSHV利用两种免疫逃避E3泛素连接酶，即K3和K5，通过泛素依赖性内吞机制下调宿主细胞中抗原呈递分子和自然杀伤（NK）细胞配体的表达。这使得受感染的细胞逃避细胞毒性淋巴细胞和NK细胞的监视和消除。报道的这些泛素连接酶的宿主细胞分子底物的数量是有限的。这些连接酶的新底物的鉴定将有助于阐明KSHV免疫逃避的机制。本研究表明，K5下调细胞表面表达的选择素，C型凝集素样粘附受体表达的淋巴细胞。色氨酸残基位于K5 RINGv结构域中E2结合位点的中心，是下调l-选择素表达所必需的。此外，位于选择素胞质尾部的赖氨酸残基是K5介导的选择素下调所必需的。K5通过多聚泛素化促进了β-选择素的降解。这些结果表明K5通过促进多聚泛素化和泛素依赖的内吞作用下调细胞表面的l-选择素表达，提示l-选择素是K5的一种新底物。此外，K3下调l-选择素表达。本研究的结果将有助于阐明KSHV的一种新的免疫逃避机制。
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic etiological factor for Kaposi’s sarcoma and primary effusion lymphoma in immunocompromised patients. KSHV utilizes two immune evasion E3 ubiquitin ligases, namely K3 and K5, to downregulate the expression of antigen-presenting molecules and ligands of natural killer (NK) cells in the host cells through an ubiquitin-dependent endocytic mechanism. This allows the infected cells to evade surveillance and elimination by cytotoxic lymphocytes and NK cells. The number of host cell molecular substrates reported for these ubiquitin ligases is limited. The identification of novel substrates for these ligases will aid in elucidating the mechanism underlying immune evasion of KSHV. This study demonstrated that K5 downregulated the cell surface expression ofl-selectin, a C-type lectin-like adhesion receptor expressed in the lymphocytes. Tryptophan residue located at the centre of the E2-binding site in the K5 RINGv domain was essential to downregulatel-selectin expression. Additionally, the lysine residues located at the cytoplasmic tail ofl-selectin were required for the K5-mediated downregulation ofl-selectin. K5 promoted the degradation ofl-selectin through polyubiquitination. These results suggest that K5 downregulatesl-selectin expression on the cell surface by promoting polyubiquitination and ubiquitin-dependent endocytosis, which indicated thatl-selectin is a novel substrate for K5. Additionally, K3 downregulatedl-selectin expression. The findings of this study will aid in the elucidation of a novel immune evasion mechanism in KSHV.