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When MARCH Family Proteins Meet Viral Infections Chunfu Zheng1,3* and Yan‑Dong Tang2

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When MARCH Family Proteins Meet Viral Infections Chunfu Zheng1,3* and Yan‑Dong Tang2 Zheng and Tang Virol J (2021) 18:49 https://doi.org/10.1186/s12985-021-01520-4 REVIEW Open Access When MARCH family proteins meet viral infections Chunfu Zheng1,3* and Yan‑Dong Tang2 Abstract Membrane‑associated RING‑CH (MARCH) ubiquitin ligases belong to a RING fnger domain E3 ligases family. Recent studies have demonstrated that MARCH proteins play critical roles during various viral infections. MARCH proteins can directly antagonize diferent steps of the viral life cycle and promote individual viral infection. This mini‑review will focus on the latest advances of MARCH family proteins’ emerging roles during viral infections. Keywords: MARCH, Antiviral, Proviral, RING fnger, E3 ligase Introduction domains. Generally, a typical MARCH protein is char- Ubiquitin is a key post-translational modifer in all acterized by two transmembrane domains, but there are eukaryotes regulating thousands of proteins and plays exceptions. MARCH5 consists of 278 amino-acid resi- important roles in physiological processes [1]. Te ubiq- dues with an amino-terminal RING fnger and four car- uitination process requires the cooperation of E1, E2, and boxy-terminal transmembrane spans [4]. MARCH6 even E3 ligases. E3 ligases are categorized based on the mech- contains 14 transmembrane helices [5]. MARCH7 and anisms of ubiquitin transfer into RING (really interest- MARCH10 have no predicted transmembrane domains ing new gene), HECT (homologous to the E6AP carboxyl [6, 7]. terminus), and RBR (RING-between RING fngers) fami- Te MARCH family proteins play important roles in lies [2]. Membrane-associated RING-CH (MARCH) fam- various biological processes, such as the turnover of ily proteins are a recently discovered subfamily of the E3 immune regulatory molecules on the plasma membrane ubiquitin ligases that harbor a catalytic domain C4HC3 [8]. Latest studies have revealed the essential functions cysteine-histidine fnger in their N-terminal cytoplasmic of MARCH proteins in the battle against multiple viral tail transmembrane domains that potentially interacts infections. MARCH proteins target viral proteins for with an E2 enzyme [3]. 11 members have been identifed, polyubiquitination and degradations through distinct and their structure is relatively conserved. Most MARCH pathways. Tis review summarizes recent progress in family proteins have similar structures: with an amino- understanding MARCH proteins’ properties and their terminal RING fnger domain, also known as the RING- emerging roles in regulating viral infection. CH domain, followed by zero, two, or more C-terminal transmembrane domains. Nine of the eleven MARCH Antiviral MARCH proteins family members (MARCH1, MARCH2, MARCH3, MARCH1/2 MARCH4, MARCH5, MARCH6, MARCH8, MARCH9, MARCH 1 and 2, two proteins of the MARCH family and MARCH11) contain hydrophobic transmembrane members, are shown to inhibit human immune defciency virus 1 (HIV-1) infection by reducing envelope glycopro- teins’ incorporation into virions [9]. Infectivity assays *Correspondence: [email protected] demonstrated that MARCH1/2 suppress viral infec- 1 Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China tion in a dose-dependent manner. Ectopic expression Full list of author information is available at the end of the article of these proteins in virus-producing cells decreased the © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zheng and Tang Virol J (2021) 18:49 Page 2 of 5 efectiveness of viral invasion and down-regulated HIV-1 infection of HIV-1 through ligase activity-dependent envelope glycoproteins from the cell surface, resulting in envelope protein degradation and/or intracellular reten- reduced penetration of envelope glycoproteins into viri- tion, a mechanism shared by MARCH8 that contributes ons. MARCH1/2 are demonstrated as antiviral factors, to the inhibition of HIV-1 infection (Fig. 1a). However, which adds these two proteins to a growing list of host unlike MARCH8 and other MARCH proteins whose factors inhibiting HIV-1 infection (Fig. 1a). Further inves- transcription is not afected during HIV infection, the tigations are required to study whether these MARCH expression of MARCH2 is substantially upregulated family members’ inhibitory activity against viral envelope upon HIV-1 infection, giving MARCH2 a unique role in glycoproteins could be related to their ability to down- monitoring and regulating the HIV-1 infection-related regulate cellular transmembrane proteins, which will biological processes. enable us to understand the molecular basis of the host defense mechanisms for these proteins. MARCH5 Interestingly, MARCH2 is shown to be upregulated Infection of hepatitis B virus (HBV) promotes chronic in HIV-1 infected cells and inhibits HIV-1 production liver disease and hepatocellular carcinoma (HCC). Te through envelope protein translocation or degrada- hepatitis B viral x (HBx) protein encoded by the HBV tion [10]. MARCH2 inhibits the virions production and genome contributes to the pathogenesis of HCC. Te Fig. 1 The antiviral functions of MARCH family proteins. a MARCH1/2 reduces envelope glycoproteins’ incorporation into virions; MARCH1/2/8 target diferent viral proteins for degradation via lysosome or autophagosome pathway. b Mitochondria ubiquitin ligase MARCH5 targets HBV HBX to degradation via the proteasome pathway. c MARCH8 inhibits EBOV glycoprotein, HIV‑1 envelope glycoprotein, and H5N1 hemagglutinin maturation and virions incorporation. HIV EnV: human immune defciency virus envelope glycoprotein; PEDV NP: porcine epidemic‑diarrhea virus nucleocapsid protein; EBOV GP: ebola virus glycoprotein; HBV HBX: hepatitis B viral protein; H5N1 HA: infuenza virus H5N1 hemagglutinin × Zheng and Tang Virol J (2021) 18:49 Page 3 of 5 high expression of MARCH5 in hepatocytes is associated terminally diferentiated myeloid cells is a potent anti- with increased survival of patients with liver cancer since viral host transmembrane protein that reduces virion it can sustain cell homeostasis and prevent a malignant incorporation of viral envelope glycoproteins. tumor. Te N-terminal RING domain of MARCH5 is Interestingly, although MARCH8 was suggested to needed to interact with and target HBx for degradation. interact with HIV-1 Env, leading to its downregulation Te lack of E3 ligase activity of MARCH5 mutant could from the producer cell surface, neither HIV-1 Vpr, Vpu, not reduce HBx protein levels. Ectopic expression of HBx nor Nef has detectable anti-MARCH8 activity, suggesting increased protein aggregates in semi-denatured deter- that HIV-1 lacks a mechanism to antagonize MARCH8 gent agarose gels, and ectopic expression of MARCH5 antiviral activity directly. HIV, especially HIV-1, may greatly resolves HBx aggregates via the proteasome- have evolved to beneft from host restriction protein dependent degradation pathway (Fig. 1b). Te develop- MARCH8. Te suppression of infectivity by MARCH8 ment of HBx-induced ROS production, mitophagy, and and other efects likely leads to a small amount of replica- cyclooxygenase-2 gene expression was suppressed when tion of HIV in macrophages, resulting in minimal cellular MARCH5 was highly expressed. Tese fndings suggest damage. Furthermore, the virus could escape from the that MARCH5 is a potential target for ameliorating HBV- host immune system and permit its survival in the host mediated liver disease [11]. [20]. Te latest study from Tokunaga’s lab showed that MARCH8 MARCH8 prevented viral infections by two diferent MARCH8 belongs to RING-fnger E3 ubiquitin ligases mechanisms. Pseudotyped VSV-G viruses, in which cyto- [12, 13]. MARCH8 downregulates many host trans- plasmic lysine residues were mutated, were insensitive to membrane proteins, including major histocompatibility the inhibitory efect of MARCH8, although those with complex (MHC)-II, CD86, interleukin (IL)-1 recep- a similar lysine mutant of HIV-1 Env remained sensi- tor accessory protein, TNF-related apoptosis-inducing tive to it. Indeed, the wild-type VSV-G, but not its lysine ligand (TRAIL) receptor 1, and the transferrin receptor mutant, was ubiquitinated by MARCH8. Besides, the [14–18]. However, its physiological functions remain MARCH8 mutant, with a disrupted cytoplasmic tyrosine unclear. motif essential for intracellular protein sorting, did not Recently, MARCH8 was identifed as a novel anti- inhibit HIV-1 Env-mediated infection while still afect- viral factor against HIV-1. Tada et al. initially noticed ing VSV-G-pseudotyped virus infection.
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