MAVS polymers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling

Abstract

Double‐stranded RNA (ds RNA ) is a potent proinflammatory signature of viral infection and is sensed primarily by RIG ‐I‐like receptors ( RLR s). Oligomerization of RLR s following binding to cytosolic ds RNA activates and nucleates self‐assembly of the mitochondrial antiviral‐signaling protein ( MAVS ). In the current signaling model, the caspase recruitment domains of MAVS form helical fibrils that self‐propagate like prions to promote signaling complex assembly. However, there is no conclusive evidence that MAVS forms fibrils in cells or with the transmembrane anchor present. We show here with super‐resolution light microscopy that MAVS activation by ds RNA induces mitochondrial membrane remodeling. Quantitative image analysis at imaging resolutions as high as 32 nm shows that in the cellular context, MAVS signaling complexes and the fibrils within them are smaller than 80 nm. The transmembrane domain of MAVS is required for its membrane remodeling, interferon signaling, and proapoptotic activities. We conclude that membrane tethering of MAVS restrains its polymerization and contributes to mitochondrial remodeling and apoptosis upon ds RNA sensing.

The Reduced Oligomerization of MAVS Mediated by ROS Enhances the Cellular Radioresistance

“…Oxidative Medicine and Cellular Longevity Buskiewicz et al reported that chemically generated oxidative stress (using glucose oxidase) stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased ATP production and spare respiratory capacity [29]. MAVS oligomerization directly suppresses the function of mitochondrial complexes I to IV and trigger the deficiency of ATP and the effusion of Cyto C [30]. Based on their findings, we speculate that MAVS involves in radiosensitivity through its oligomerization mediated by ROS.…”

Mitochondria as intracellular signaling platforms in health and disease

“…It is well established that MAVS is C-terminally anchored on the OMM and that the formation of large MAVS aggregates causes substantial changes to mitochondrial morphology ( Cai et al, 2014 ; Hou et al, 2011 ; Xu et al, 2015 ). Even endogenous levels of MAVS aggregates are sufficient to drive apoptosis, which is dependent on the MAVS transmembrane domain, likely linked to MAVS-driven mitochondrial fragmentation ( Hwang et al, 2019 ). Driving such morphological changes are MAVS-dependent mitochondrial ROS generation, mitochondrial membrane hyperpolarization, inhibition of spare respiratory capacity, and modulation of ATP synthesis (see below; Buskiewicz et al, 2016 ; Lei et al, 2009 ).…”

MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity

“…1a, b, "poly(I:C)-LMW"), suggesting that Mff plays a critical role in the MAVS-mediated antiviral response. Mitochondrial morphological changes after the viral RNA introduction 27,29,43,44 were severely repressed in Mff KO MEFs and in Drp1 KO MEFs ( Supplementary Fig. 1e).…”