Identification of the gC1qR sites for the HIV-1 viral envelope protein gp41 and the HCV core protein: Implications in viral-specific pathogenesis and therapy.
Identification of the gC1qR sites for the HIV-1 viral envelope protein gp41 and the HCV core protein: Implications in viral-specific pathogenesis and therapy.
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DOI：
10.1016/j.molimm.2016.03.016
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发表时间：
2016-06
影响因子：
3.6
通讯作者：
Ghebrehiwet B
中科院分区：
文献类型：
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作者：
Pednekar L;Valentino A;Ji Y;Tumma N;Valentino C;Kadoor A;Hosszu KK;Ramadass M;Kew RR;Kishore U;Peerschke EI;Ghebrehiwet B
过去20年来积累的大量证据支持gC 1 qR是主要病原体相关模式识别受体（PRR）的概念。这一结论是基于这样的事实，即广泛的细菌和病毒配体能够利用gC 1 qR来抑制宿主的免疫反应，从而提高它们的存活率，或者进入细胞引发疾病。在对gC 1 qR具有亲和力的大量病毒配体中，HIV-1包膜糖蛋白gp 41和丙型肝炎病毒（HCV）的核心蛋白是主要的关注点，因为已知它们导致由这些病原体引起的高发病率和死亡率。虽然HCV核心蛋白结合gC 1 qR并抑制T细胞增殖，导致免疫应答显著减弱，但gp 41利用gC 1 qR诱导NK细胞配体NKp 44 L在未感染的CD 4 + T细胞上的表面表达，从而使它们易于被表达NKp 44受体的NK细胞自体破坏。由于肽或抗体为基础的治疗方案的设计的潜力，目前的研究进行，以确定这些病原体相关的分子配体的gC 1 qR相互作用位点。采用固相微孔板结合试验，我们研究了每种病毒配体与野生型gC 1 qR和11 gC 1 qR缺失突变体的结合。从这些研究中获得的结果已经确定了两个主要的HCV核心蛋白位点的gC 1 qR的结构域，包括残基144-148和196-202。结构域196-202依次位于由外显子IV-VI（残基159-282）编码的较大gC 1 qR区段的后半部分，其先前被提出含有HCV核心蛋白的位点。另一方面，发现gp 41的主要gC 1 qR位点位于由外显子IV编码的高度保守区域中，并且由残基174-180组成。有趣的是，gC 1 qR残基174-180也构成可溶性gC 1 qR（sgC 1 qR）的细胞表面结合位点，其可以通过表面表达的纤维蛋白原或其他膜分子以自分泌/旁分泌方式结合到细胞表面。因此，这些病毒配体的位点的鉴定应该为基于肽或基于抗原的治疗策略的设计提供额外的靶标。
A substantial body of evidence accumulated over the past 20 years supports the concept that gC1qR is a major pathogen-associated pattern recognition receptor (PRR). This conclusion is based on the fact that, a wide range of bacterial and viral ligands are able to exploit gC1qR to either suppress the host’s immune response and thus enhance their survival, or to gain access into cells to initiate disease. Of the extensive array of viral ligands that have affinity for gC1qR, the HIV-1 envelope glycoprotein gp41, and the core protein of hepatitis C virus (HCV) are of major interest as they are known to contribute to the high morbidity and mortality caused by these pathogens. While the HCV core protein binds gC1qR and suppresses T cell proliferation resulting in a significantly diminished immune response, the gp41 employs gC1qR to induce the surface expression of the NK cell ligand, NKp44L, on uninfected CD4+ T cells, thereby rendering them susceptible to autologous destruction by NKp44 receptor expressing NK cells. Because of the potential for the design of peptide-based or antibody-based therapeutic options, the present studies were undertaken to define the gC1qR interaction sites for these pathogen-associated molecular ligands. Employing a solid phase microplate-binding assay, we examined the binding of each viral ligand to wild type gC1qR and 11 gC1qR deletion mutants. The results obtained from these studies have identified two major HCV core protein sites on a domain of gC1qR comprising of residues 144–148 and 196–202. Domain 196–202 in turn, is located in the last half of the larger gC1qR segment encoded by exons IV–VI (residues 159–282), which was proposed previously to contain the site for HCV core protein. The major gC1qR site for gp41 on the other hand, was found to be in a highly conserved region encoded by exon IV and comprises of residues 174–180. Interestingly, gC1qR residues 174–180 also constitute the cell surface-binding site for soluble gC1qR (sgC1qR), which can bind to the cell surface in an autocrine/paracrine manner via surface expressed fibrinogen or other membrane molecules. The identification of the sites for these viral ligands should therefore provide additional targets for the design of peptide-based or antigen-based therapeutic strategies.