Mitochondrial import receptor subunit TOM70 (TOMM70) recognizes mitochondrial protein precursors in the cytosol and mediates their translocation to the mitochondrial compartments (reviewed in Fan ACY & Young JC et al. 2011; Sokol AM et al. 2014; Kreimendahl S & Rassow J 2020). The molecular chaperone complexes of heat shock protein 90 kDa (HSP90) and HSP70 were shown to deliver precursor proteins to TOMM70 for subsequent import (Young JC et al. 2003; Zanphorlin LM et al. 2016). Mitochondrial import receptor subunit TOM20 (TOMM20) competes with HSC70 (HSPA8) and HSP90 for TOMM70 binding (Fan ACY et al. 2011).
During viral infection, cytosolic viral RNA triggers activation of mitochondrial antiviral-signaling protein (MAVS) and the formation of MAVS signalosome (Kawai T et al. 2005; Seth RB et al. 2005; Xu LG et al. 2005). MAVS localizes on the outer membrane of mitochondria through its C-terminal transmembrane (TM) domain. Activated MAVS recruits TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) to mitochondria leading to the activation of IRF3 and subsequent production of type I interferons. MAVS activates TBK1 in the TNF receptor-associated factors (TRAF)-dependent manner (Liu S et al. 2013; Fang R et al. 2017). Further, NF-kappa-B essential modulator (NEMO) links TBK1 to MAVS via TANK (Zhao T et al. 2007; Fang R et al. 2017).
Immunoprecipitation assays coupled to mass spectrometry analysis revealed that TOMM70 interacted with exogenously expressed MAVS in Sendai virus (SeV)-stimulated human embryonic kidney (HEK293) cells (Liu XY et al. 2010). The TM domains of both MAVS and TOMM70 were required for their interaction. In addition, TOMM70 interacted strongly with the C-terminal motif (EEVD) of HSP90 (Liu XY et al. 2010; Gava LM et al. 2011). TOMM70 also co-immunoprecipitated with TBK1 and IRF3 in HEK293 cells (Liu XY et al. 2010). Further, both TBK1 and IRF3 associated with HSP90, which facilitated signal transduction from TBK1 to IRF3 in SeV-infected HEK293 cells (Yang K et l. 2006). Moreover, SeV infection enhanced the interaction between IRF3 and apoptosis regulator BAX (BAX) in HEK293T cells (Wei B et al. 2015). In SeV-stimulated HEK293 cells, cytosolic BAX translocated to the mitochondrial outer membrane and induced apoptosis in the IRF3-dependent manner via the formation of the TOMM70:HSP90:IRF3:BAX protein complex (Wei B et al. 2015). Knockdown of HSP90 by small interfering RNA (siRNA) decreased the association of TOMM70 with TBK1 and IRF3 (Liu XY et al. 2010). Overexpression of TOMM70 enhanced mRNA levels of IRF3-responsive genes (including IFNB, IFIT1 and RANTES) in HEK293 cells during SeV infection or poly(I:C) stimulation, whereas knockdown of TOMM70 by siRNA showed an inhibitory effect. Similar results were obtained in murine bone marrow-derived macrophages (BMDM) and bone marrow-derived dendritic cells (BMDC) (Liu XY et al. 2010). Thus, the association of MAVS with TOMM70 is thought to potentiate the HSP90-mediated recruitment of TBK1and IRF3 to mitochondria during viral infection thereby inducing IRF3-mediated host antiviral responses.
SARS-CoV-2 9b interaction with TOMM70 inhibits binding of HSP90 to TOMM70 (Jiang HW et al. 2020).