The emerging roles of MARCH8 in viral infections: A double-edged Sword

Abstract

The host cell membrane-associated RING-CH 8 protein (MARCH8), a member of the E3 ubiquitin ligase family, regulates intracellular turnover of many transmembrane proteins and shows potent antiviral activities. Generally, 2 antiviral modes are performed by MARCH8. On the one hand, MARCH8 catalyzes viral envelope glycoproteins (VEGs) ubiquitination and thus leads to their intracellular degradation, which is the cytoplasmic tail (CT)-dependent (CTD) mode. On the other hand, MARCH8 traps VEGs at some intracellular compartments (such as the trans-Golgi network, TGN) but without inducing their degradation, which is the cytoplasmic tail-independent (CTI) mode, by which MARCH8 hijacks furin, a cellular proprotein convertase, to block VEGs cleavage. In addition, the MARCH8 C-terminal tyrosine-based motif (TBM) 222YxxL225 also plays a key role in its CTI antiviral effects. In contrast to its antiviral potency, MARCH8 is occasionally hijacked by some viruses and bacteria to enhance their invasion, indicating a duplex role of MARCH8 in host pathogenic infections. This review summarizes MARCH8's antiviral roles and how viruses evade its restriction, shedding light on novel antiviral therapeutic avenues.

Fig 1. Schematic structure of human MARCH1, MARCH2, and MARCH8.

(A) Primary structure of human MARCH1, MARCH2, and MARCH8. The human MARCH1, MARCH2, and MARCH8 contained an N-terminus RING domain, 2 TMs, an extracellular loop, and a C-terminus cytoplasmic tail. (B) Membrane-associated structure of human MARCH1, MARCH2, and MARCH8. Two TBMs, ²²²YVQL²²⁵ and ²³²YNRV²³⁵, are located in the C-terminus of MARCH1 and MARCH8. C-CT, C-terminus cytoplasmic tail; ECL, extracellular loop; N-CT, N-terminus cytoplasmic tail; PM, plasma membrane; RING, E3 ubiquitin ligase domain; TBM, tyrosine-based motif; TM, transmembrane domain.

Fig 2. The MARCH8 CTD antiviral mode.

MARCH8 generally recognized viral proteins’ cytoplasmic tail lysine residues and catalyzed their polyubiquitination, which thus induced these viral proteins’ translocation from the cell PM and entering into the lysosome pathway for degradation. Other viral glycoproteins targeted by MARCH8 via the CTD mode shared a similar degradation route to VSV-G and IAV H1N1 M2. CTD, cytoplasmic tail-dependent; PM, plasma membrane; Ub, ubiquitin; VSV-G, vesicular stomatitis virus G-glycoprotein.

Fig 3. MARCH8 regulated viral protein autophagy pathway.

After entry into host cells, the PEDV N protein was recognized and hijacked by a series of host proteins, such as IRAV, PRPF19, and HNRNPK. These host antiviral proteins recruited MARCH8 to ubiquitinate PEDV N protein and combined with CALCOCO2 to form a cellular complex directed to autophagosome (lysophagosome)/proteasome for degradation. In addition, the host proteins, including TARDBP, FUBP3, HNRNPA1, and HNRNPK, also activated the production of cellular type-I IFN, which enhanced the host cell antiviral immunity responses. AVF, antiviral factor; IRF3, interferon regulatory factor 3; PEDV, porcine epidemic diarrhea virus; PM, plasma membrane; TBK1, TANK binding kinase 1; Ub, ubiquitination.

Fig 4. The MARCH8 CTI antiviral mode.

This figure is adapted from Fig 3 of a previous publication [28]. MARCH8 employed the TBM-dependent (type-I) and furin-dependent (type-II) CTI modes to restrict HIV-1 Env and EBOV GP activities, respectively. Under the type-I CTI mode, HIV-1 Env was down-regulated by MARCH8 from the cell PM, where it was translocated to and trapped at the TGN apparatus. However, under the type-II CTI mode, EBOV GP was retained by MARCH8 at the TGN apparatus, where it was prevented from anterograde transport to the cell PM. Simultaneously, the EBOV GP cellular cleavage and glycosylation maturation were also blocked by MARCH8 at the TGN. Human MARCH8 probably restricts SARS-CoV-2 S and IAV H5N1 HA through the type-II CTI antiviral mode. CTI, cytoplasmic tail-independent; HA, hemagglutinin; IAV, influenza A virus; PM, plasma membrane; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; TBM, tyrosine-based motif; TGN, trans-Golgi network.