Mitochondrial Ubiquitin Ligase MARCH5 Promotes TLR7 Signaling by Attenuating TANK Action

Abstract

The signaling of Toll-like receptors (TLRs) is the host's first line of defense against microbial invasion. The mitochondrion is emerging as a critical platform for antiviral signal transduction. The regulatory role of mitochondria for TLR signaling remains to be explored. Here, we show that the mitochondrial outer-membrane protein MARCH5 positively regulates TLR7 signaling. Ectopic expression or knockdown of MARCH5 enhances or impairs NF-κB-mediated gene expression, respectively. MARCH5 interacts specifically with TANK, and this interaction is enhanced by R837 stimulation. MARCH5 catalyzes the K63-linked poly-ubiquitination of TANK on its Lysines 229, 233, 280, 302 and 306, thus impairing the ability of TANK to inhibit TRAF6. Mislocalization of MARCH5 abolishes its action on TANK, revealing the critical role of mitochondria in modulating innate immunity. Arguably, this represents the first study linking mitochondria to TLR signaling.

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

“…[1][2][3][4][5][6][7][8][9][10][11][47][48][49][50] Several studies suggest that pre-or perinatal exposure to certain triggers might imprint a state of both dysregulated immune response and mitochondrial dysfunction in the progeny as a result of the integration of basic mitochondrial functions with the immune response and antioxidant defense mechanisms. [51][52][53][54][55] Furthermore, maternal exposure during pregnancy to various pathogens and/or the maternal immune response (fever, inflammation) have been associated with significant increased risk of autism spectrum disorder (ASD). [56][57][58][59] In this regard, gestational exposure to the viral mimetic poly(I:C) in rodents resulted in ASD-like behavioral abnormalities in the progeny, 60 and immune cells from the same animals had OXPHOS deficits still present in adulthood.…”

MARCH5 gene is duplicated in rainbow trout, but only fish-specific gene copy is up-regulated after VHSV infection

“…Firstly, MARCH5 regulates mitochondrial fission and fusion [11]. Secondly, MARCH5 affects TLR signalling [14]. It might be assumed that piscine MARCH5 proteins share the original functions of ancestral MARCH5 factor, i.e.…”

“…The balanced regulation of mitochondrial fission and fusion rates contributes to the cellular fitness concerning for example essential mechanisms like Ca 2þ buffering [13]. Recently, it has been shown that human MARCH5 protein positively regulates TLR7 signaling by ubiquitination of TANK (TRAF family member-associated NF-kB activator) [14]. TANK is known as an inhibitor of TLR-dependent NF-kB activation by suppressing the autoubiquitination of the downstream factor TRAF6 (TNF receptorassociated factor 6).…”

Sensing and responding to cytosolic viruses invasions: An orchestra of kaleidoscopic ubiquitinations

“…1B) [4]. K48-linked poly-ubiquitination generally targets the substrates for proteasomal degradation, whereas K63-linked poly-ubiquitination modulates non-proteolytic processes including membrane trafficking and signal transduction [5][6][7][8].…”