The Mitochondrial Proteins NLRX1 and TUFM Form a Complex that Regulates Type I Interferon and Autophagy

Abstract

SUMMARY The mitochondrial protein MAVS (also known as IPS-1, VISA, CARDIF) interacts with RLR (RIG-I-like receptors) to induce type 1 interferon (IFN-I) during viral infection. NLRX1 is a mitochondrial NLR (nucleotide-binding, leucine-rich repeats containing) protein that attenuates MAVS-RLR signaling. Using Nlrx1−/− cells we confirmed NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1, and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM.

Inflammasomes and its importance in viral infections

“…TUFM further interacts with Atg5-Atg12 and Atg16L1, promotes autophagy, and shares the function of NLRX1 in inhibiting RLR-induced IFN-I, given that increased IFN-I and decreased autophagy has been demonstrated during stomatitis virus infection in the absence of NLRX1, which provides an advantage for host defence against vesicular stomatitis virus infection [105,106]. Recently, NLRX1 has shown to defend the macrophage cells from apoptosis due to influenza virus by interacting with apoptotic protein PB1-F2 and promoting IFN signalling.…”

Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure

“…NLRP12 functions as a negative regulator of inflammation by modulating elements of the NF-k B signalling pathway ( Fig. 3) (Allen et al, 2012a, b;Arthur et al, 2007;Lei et al, 2012Lei et al, , 2013Moore et al, 2008;Tsuchiya et al, 2010;Wagner et al, 2009;Xia et al, 2011;Zaki et al, 2014). This hypothesis is supported by recent in vivo studies utilizing Nlrp12 2/2 mice in models of acute colitis and colitis-associated tumorigenesis.…”

“…Intracytoplasmic virions can be captured within the autophagy pathway and transferred to lysosomes for eventual breakdown and/or pattern recognition resulting in the activation of innate and adaptive immune responses (Shoji-Kawata and Levine, 2009). NLRX1's promotion and regulation of autophagy has been reported in several instances within the context of virus exposure (Lei et al, 2012(Lei et al, , 2013. These studies revealed that NLRX1 is capable of augmenting autophagy pathways by associating with the Tu translation elongation factor (TUFM) protein (Lei et al, 2012).…”

“…NLRX1's promotion and regulation of autophagy has been reported in several instances within the context of virus exposure (Lei et al, 2012(Lei et al, , 2013. These studies revealed that NLRX1 is capable of augmenting autophagy pathways by associating with the Tu translation elongation factor (TUFM) protein (Lei et al, 2012). TUFM is a molecule that not only potently suppresses RIG-I signalling, but is also associated with the autophagy complex ATG12-ATG5-ATG16L1.…”

“…TUFM is a molecule that not only potently suppresses RIG-I signalling, but is also associated with the autophagy complex ATG12-ATG5-ATG16L1. NLRX1 and TUFM appear to act together to keep type I IFN production in check and also prevent decreases in autophagy (Lei et al, 2012(Lei et al, , 2013. The ATG12-ATG5 complex can also interact directly with MAVS to inhibit type I IFN.…”