Mahon Cathal, Krogan Nevan J, Craik Charles S, Pick Elah
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158-2530, USA.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158-2530, USA.
Biomolecules. 2014 Oct 13;4(4):897-930. doi: 10.3390/biom4040897.
The ability of viruses to subvert host pathways is central in disease pathogenesis. Over the past decade, a critical role for the Ubiquitin Proteasome System (UPS) in counteracting host immune factors during viral infection has emerged. This counteraction is commonly achieved by the expression of viral proteins capable of sequestering host ubiquitin E3 ligases and their regulators. In particular, many viruses hijack members of the Cullin-RING E3 Ligase (CRL) family. Viruses interact in many ways with CRLs in order to impact their ligase activity; one key recurring interaction involves re-directing CRL complexes to degrade host targets that are otherwise not degraded within host cells. Removal of host immune factors by this mechanism creates a more amenable cellular environment for viral propagation. To date, a small number of target host factors have been identified, many of which are degraded via a CRL-proteasome pathway. Substantial effort within the field is ongoing to uncover the identities of further host proteins targeted in this fashion and the underlying mechanisms driving their turnover by the UPS. Elucidation of these targets and mechanisms will provide appealing anti-viral therapeutic opportunities. This review is focused on the many methods used by viruses to perturb host CRLs, focusing on substrate sequestration and viral regulation of E3 activity.
病毒颠覆宿主通路的能力在疾病发病机制中至关重要。在过去十年中，泛素蛋白酶体系统（UPS）在病毒感染期间对抗宿主免疫因子方面的关键作用已显现出来。这种对抗通常是通过表达能够隔离宿主泛素E3连接酶及其调节剂的病毒蛋白来实现的。特别是，许多病毒劫持了Cullin-RING E3连接酶（CRL）家族的成员。病毒与CRL以多种方式相互作用，以影响其连接酶活性；一种反复出现的关键相互作用涉及将CRL复合物重新导向，以降解在宿主细胞内原本不会被降解的宿主靶标。通过这种机制去除宿主免疫因子为病毒繁殖创造了更适宜的细胞环境。迄今为止，已鉴定出少数靶标宿主因子，其中许多是通过CRL-蛋白酶体途径降解的。该领域正在进行大量工作，以揭示以这种方式靶向的更多宿主蛋白的身份以及驱动其被UPS周转的潜在机制。阐明这些靶标和机制将提供有吸引力的抗病毒治疗机会。本综述重点关注病毒用于干扰宿主CRL的多种方法，重点是底物隔离和E3活性的病毒调节。
