SARS-Coronavirus Open Reading Frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome

Abstract

Coronaviruses (CoV) have recently emerged as potentially serious pathogens that can cause significant human morbidity and death. The severe acute respiratory syndrome (SARS)-CoV was identified as the etiologic agent of the 2002-3 international SARS outbreak. Yet how SARS evades innate immune responses to cause human disease remains poorly understood. Here, we show that a protein encoded by SARS-CoV designated as open reading frame-9b (ORF-9b) localizes to mitochondria and causes mitochondrial elongation by triggering ubiquitination and proteasomal degradation of dynamin-like protein (DRP1), a host protein involved in mitochondrial fission. Also, acting on mitochondria ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping poly(C)-binding protein 2 (PCBP2) and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF6. This severely limits host cell interferon responses. Reducing either PCBP2 or AIP4 expression substantially reversed the ORF-9b mediated reduction of MAVS and the suppression of anti-viral transcriptional responses. Finally, transient ORF-9b expression led to a strong induction of autophagy in cells. The induction of autophagy depended upon ATG5, a critical autophagy regulator, but the inhibition of MAVS signaling did not. These results indicate that SARS-CoV ORF-9b manipulates host cell mitochondria and mitochondrial function to help evade host innate immunity. This study has uncovered an important clue to the pathogenesis of SARS-CoV infection and illustrates the havoc that a small open reading frame can cause in cells.

Spring Viremia of Carp Virus N Protein Suppresses Fish IFNφ1 Production by Targeting the Mitochondrial Antiviral Signaling Protein

“…Interestingly, many viruses possess different strategies to suppress MAVS signaling, including cleaving MAVS from the mitochondria, assembling a degradasome to disable MAVS and disrupting the function of MAVS-containing complexes (14,15,45). Compared with other molecules, choosing MAVS as the target seems to be preferred by viruses.…”

“…pro of coxsackievirus B3 (12,13), or degraded by the hepatitis B virus X and open reading frame (ORF)-9b of coronaviruses in an ubiquitin (Ub)-proteasome manner (14,15).…”

Heixuedian (heix), a potential melanotic tumor suppressor gene, exhibits specific spatial and temporal expression pattern during drosophila hematopoiesis

“…Besides supplying cellular energy, mitochondria is involved in many other biological process such as cellular differentiation, programmed cell death (apoptosis), antiviral responses as well as the control of the cell cycle and cell growth (Chan, 2006;McBride et al, 2006). Moreover, it was reported recently that mitochondria is involved in a broad range of innate immune pathways, such as NF-κB pathway and Toll pathway, and acts as signaling platforms and masters of the innate immune response (Goswami et al, 2013;Shi et al, 2014;Wang and Weinman, 2013). Furthermore, UBIAD1/Heix is a prenyltransferase with vitamin K2 synthetase activity, while vitamin K2 acts as a mitochondrial electron carrier and can rescue mitochondria defects in heix mutant (Vos et al, 2012).…”

The role of mitochondrial dysfunction in age-related diseases

“…Accordingly, PB1-F2 888 translocation correlates with subdued innate immunity [166]. The [167]. There is also evidence that hepatitis C affects mitochondria by 893 suppressing mitophagy, triggering mitochondrial fission, and preventing 894 apoptosis [168,169].…”