Human Cytomegalovirus vMIA Inhibits MAVS Oligomerization at Peroxisomes in an MFF-Dependent Manner

Abstract

Upon intracellular recognition of viral RNA, RIG-I-like proteins interact with MAVS at peroxisomes and mitochondria, inducing its oligomerization and the downstream production of direct antiviral effectors. The human cytomegalovirus (HCMV) is able to specifically evade this antiviral response, via its antiapoptotic protein vMIA. Besides suppressing the programmed cell death of infected cells, vMIA inhibits the antiviral signalling at mitochondria by inducing the organelle’s fragmentation, consequently hindering the interaction between MAVS and the endoplasmic reticulum protein STING. Here we demonstrate that vMIA interferes with the peroxisomal antiviral signalling via a distinct mechanism that is independent of the organelle’s morphology and does not affect STING. vMIA interacts with MAVS at peroxisomes and inhibits its oligomerization, restraining downstream signalling, in an MFF-dependent manner. This study also demonstrates that vMIA is totally dependent on the organelle’s fission machinery to induce peroxisomal fragmentation, while this dependency is not observed at mitochondria. Furthermore, although we demonstrate that vMIA is also able to inhibit MAVS oligomerization at mitochondria, our results indicate that this process, such as the whole vMIA-mediated inhibition of the mitochondrial antiviral response, is independent of MFF. These observed differences in the mechanisms of action of vMIA towards both organelles, likely reflect their intrinsic differences and roles throughout the viral infection. This study uncovers specific molecular mechanisms that may be further explored as targets for antiviral therapy and highlights the relevance of peroxisomes as platforms for antiviral signalling against HCMV.

The physiological functions of human peroxisomes

“…vMIA has also been shown to inhibit antiviral signaling at both organelles by directly interfering with MAVS oligomerization. This process was found to be dependent on Mff at the peroxisomes, but independent of MFF at mitochondria (463). An increased localization of vMIA to peroxisomes was observed throughout infection, culminating in the modulation of peroxisome morphology late in infection through the activation of PEX11β (464).…”

Peroxisomes : novel findings and future directions

“…Ferreira and colleagues proposed a model in which HCMV’s protein vMIA interacts with the peroxisomal biogenesis factor PEX19 at the cytoplasm to travel to peroxisomes, where it interacts with the antiviral signaling protein MAVS. This interaction interferes, in a MFF-dependent manner, with the formation of MAVS oligomers, and inhibits the consequent activation of the downstream antiviral signaling (Ferreira et al 2022a ). Their results show the relevance of peroxisomes as platforms for antiviral signaling against HCMV and unravel specific molecular mechanisms that may be further explored as targets for antiviral therapy.…”

Influenza A virus activates the unfolded protein response and induces the accumulation of insoluble protein aggregates that are essential for efficient viral propagation

“…As most RNA viruses, IAV is mainly sensed by the RIG-I/MAVS antiviral signaling pathway [39], which culminates in the production of interferons (IFNs) or IFN-stimulated genes (ISG) that restrict the virus life cycle and warn the neighboring cells for the presence of the pathogen [40]. To determine whether HASQ-6Cl intensifies this antiviral signaling response, we analyzed the levels of IFNβ and the ISG IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) in A549 cells upon transfection of RIG-I-CARD (a constitutively active form of RIG-I stimulates the RIG-I/MAVS pathway [41][42][43], in the absence or presence of HASQ-6Cl. Our results demonstrate that there is no significant difference between IFNβ or IFIT1 production in the presence of HASQ-6Cl (Fig.…”