HIV-1 Nef down-modulates C-C and C-X-C chemokine receptors via ubiquitin and ubiquitin-independent mechanism.
HIV-1 Nef down-modulates C-C and C-X-C chemokine receptors via ubiquitin and ubiquitin-independent mechanism.
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DOI：
10.1371/journal.pone.0086998
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Venkatesan S
中科院分区：
文献类型：
--
作者：
Chandrasekaran P;Moore V;Buckley M;Spurrier J;Kehrl JH;Venkatesan S
人类和猿猴免疫缺陷病毒(HIV-1、HIV-2和SIV)编码一种辅助蛋白Nef，它是一种致病和毒力因子。NEF是一种多价适配子，可调节包括趋化因子受体(CKRs)在内的许多免疫细胞受体的运输。激动剂占据的CXCR4的生理内吞路线包括三个关键赖氨酸残基上磷酸化受体的泛素化，以及动力蛋白依赖的ESCRT途径运输到溶酶体进行降解。同样，Nef诱导的CXCR4降解严重依赖于C端SSLKILSKGK基序中的三个赖氨酸。NEF在静息状态下直接招募Hect结构域E3连接酶AIP4或NEDD4到CXCR4。通过Nef、CXCR4与AIP4或NEDD4的三元相互作用，通过表达催化失活的AIP4-C830A突变体逆转Nef效应，以及通过下调AIP4、NEDD4或某些ESCRT-0适配子的siRNA，证实了这一机制。然而，依赖泛素化的溶酶体降解并不是Nef下调CKRs的唯一机制。激动剂和Nef介导的CXCR2(和CXCR1)降解不依赖泛素化。NEF还通过泛素化不依赖的机制，显著下调了与突发综合征相关的自然截短的CXCR4，以及抵抗CXCL12诱导的内化的CXCR4的工程变体。
Human and Simian Immunodeficiency virus (HIV-1, HIV-2, and SIV) encode an accessory protein, Nef, which is a pathogenesis and virulence factor. Nef is a multivalent adapter that dysregulates the trafficking of many immune cell receptors, including chemokine receptors (CKRs). Physiological endocytic itinerary of agonist occupied CXCR4 involves ubiquitinylation of the phosphorylated receptor at three critical lysine residues and dynamin-dependent trafficking through the ESCRT pathway into lysosomes for degradation. Likewise, Nef induced CXCR4 degradation was critically dependent on the three lysines in the C-terminal -SSLKILSKGK- motif. Nef directly recruits the HECT domain E3 ligases AIP4 or NEDD4 to CXCR4 in the resting state. This mechanism was confirmed by ternary interactions of Nef, CXCR4 and AIP4 or NEDD4; by reversal of Nef effect by expression of catalytically inactive AIP4-C830A mutant; and siRNA knockdown of AIP4, NEDD4 or some ESCRT-0 adapters. However, ubiquitinylation dependent lysosomal degradation was not the only mechanism by which Nef downregulated CKRs. Agonist and Nef mediated CXCR2 (and CXCR1) degradation was ubiquitinylation independent. Nef also profoundly downregulated the naturally truncated CXCR4 associated with WHIM syndrome and engineered variants of CXCR4 that resist CXCL12 induced internalization via an ubiquitinylation independent mechanism.
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