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Review
. 2020 Apr 26;12(5):487.
doi: 10.3390/v12050487.

Multifaceted Functions of Host Cell Caveolae/Caveolin-1 in Virus Infections

Yifan Xing  1   2 , Zeyu Wen  1   2 , Wei Gao  1   2 , Zhekai Lin  1   2 , Jin Zhong  2   3 , Yaming Jiu  1   2
Affiliations
Review

Multifaceted Functions of Host Cell Caveolae/Caveolin-1 in Virus Infections

Yifan Xing et al. Viruses. .

Abstract

Virus infection has drawn extensive attention since it causes serious or even deadly diseases, consequently inducing a series of social and public health problems. Caveolin-1 is the most important structural protein of caveolae, a membrane invagination widely known for its role in endocytosis and subsequent cytoplasmic transportation. Caveolae/caveolin-1 is tightly associated with a wide range of biological processes, including cholesterol homeostasis, cell mechano-sensing, tumorigenesis, and signal transduction. Intriguingly, the versatile roles of caveolae/caveolin-1 in virus infections have increasingly been appreciated. Over the past few decades, more and more viruses have been identified to invade host cells via caveolae-mediated endocytosis, although other known pathways have been explored. The subsequent post-entry events, including trafficking, replication, assembly, and egress of a large number of viruses, are caveolae/caveolin-1-dependent. Deprivation of caveolae/caveolin-1 by drug application or gene editing leads to abnormalities in viral uptake, viral protein expression, or virion release, whereas the underlying mechanisms remain elusive and must be explored holistically to provide potential novel antiviral targets and strategies. This review recapitulates our current knowledge on how caveolae/caveolin-1 functions in every step of the viral infection cycle and various relevant signaling pathways, hoping to provide a new perspective for future viral cell biology research.

Keywords: caveolae; caveolin-1; signaling pathway; virus assembly; virus egress; virus entry; virus life cycle; virus replication; virus trafficking.

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Conflict of interest statement

All the authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Caveolae/CAV-1 play critical roles in the entry of viruses to the host cells. (A) Firstly, the virus binds to a specific receptor in caveolae microdomain. The receptors involved in endocytosis are specifically described and listed. CD13, MHC class I, α2β1 integrin, and HS are involved in caveolae-mediated endocytosis, while integrins participate in clathrin-mediated endocytosis of foot-and-mouth disease virus (FMDV). (B) Subsequently, viruses internalize through the caveolae-mediated endocytic pathway are divided into four categories according to their structures and hosts. (C) It is noteworthy that transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) were reported to complete endocytosis by both caveolae- and clathrin-mediated pathways. (D,E) Inhibitors of clathrin- and caveolae-mediated endocytosis and their related functions are described and listed.
Figure 2
Figure 2
Multifunctional roles of caveolae/CAV-1 in the life cycle of corresponding viruses. (A) Trafficking: CAV-1 is involved in the complicated trafficking network of viruses. There is host cell type-, virus type-dependent crosstalk between caveosome trafficking and endosome trafficking, despite different endocytic pathways (caveolae- or clathrin-mediated) that viruses hijack. In addition to viral particles, CAV-1 is also involved in regulating the sorting and transport of viral components/proteins. (B) Replication: caveolae and CAV-1 facilitate the targeted location of virions, viral proteins, and host-related proteins to lipid rafts-associated compartments to complete viral replication. (C) Assembly and egress: caveolae and CAV-1 are involving in virus release and might incorporate into the enveloping process of some mature virus particles. The chromatic wireframes indicate the reported viruses involved in these processes. Numbers in square brackets indicate the relative references.
Figure 3
Figure 3
Summary of caveolae/CAV-1 in signal transduction during virus infection. A total of 16 caveolae and CAV-1-related signaling pathways from 11 viruses are shown in this figure. Different viruses and involved signaling pathways associated with caveolae and CAV-1 are represented in different colors to distinguish among complex networks. (A,B) The internalization of the Japanese encephalitis virus (JEV) into SK-N-SH cells activates the EGFR-PI3K-RhoA-ROCK-CFL1 signaling pathway and leads CAV-1 phosphorylation and furthers Rac1 activation, thereby initiating PAK1-CFL1-mediated actin polymerization and JEV internalization [18]. The entry of Avian reovirus (ARV) also takes advantage of the phosphorylation of CAV-1 and Rac1 activation, while by activating p38 MAPK and Src kinase [54]. (C) The transient depolymerization of the actin stress fibers causes the formation of actin tails, which depends on the local tyrosine phosphorylation of caveolae after SV40 infection [9,10,11,12,13,14]. (D) Venezuelan equine encephalitis virus (VEEV) and western equine encephalitis virus (WEEV) successfully cross the BBB with the help of IFN and RhoA GTPase signaling pathways via CAV-1-mediated transcytosis [109]. (E) CAV-1 plays a variety of roles during HIV-1 infection. Tat protein can activate the Ras signaling pathway, making HIV successfully cross the BBB with the dependency on CAV-1 [93]. The interaction between CAV-1 and Tat also results in less occludin and LRP-1 expression and more RAGE and RhoA production, thus making Aβ deposition in the brain [94]. In addition, CAV-1 restricts HIV infection in many ways. Firstly, CAV-1 inhibits HIV-1 replication by suppressing NF-κB p65 acetylation, which is indispensable for inflammatory response activation [80]. Secondly, CAV-1 could interact with HIV Nef protein to activate cholesterol efflux, thus leading to an impaired HIV infectivity [95]. Besides, Nef protein is also involved in inducing CAV-1 phosphorylation and further affecting its redistribution [96]. Lastly, CAV-1 reduces HIV infection by interacting with gp41, mainly through inhibition of Env-induced membrane hemifusion [97]. (F) CAV-1 plays a role in tumor angiogenesis through participates in VEGF-mediated signaling pathways during HBV infection [99]. In in vitro transfected HBx rather than an actual infection, CAV-1 expression was inhibited by promoting the methylation of CpG islands on its promoter region [101]. (G–J) iNOS, ROS, and p53 construct a complex network since they are involved in different CAV-1-related pathways during virus infections. In the case of HSV infection, CAV-1 plays a positive role in the infection via interacting with iNOS to inhibit the production of nitric oxide [103]. During PRRSV infection, less CAV-1 and higher levels of HSP90 are found to be responsible for the increasing levels of iNOS. Increased iNOS further results in higher ROS generation and endothelial dysfunction [104]. In CAV-1-lack cells, ROS and p53 are upregulated and cause an increase of IVA virion yield during IVA infection [105]. Moreover, the E6 protein of HPV16 could downregulate CAV-1 via p53-inactivating, which eventually causes malignant transformation [106]. Numbers in square brackets indicate the relative references.
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