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). Activated MAVS recruits TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3) and IRF7 to the mitochondria leading to the activation of IRF3/IRF7 and subsequent production of type I interferons (Kawai T et al. 2005; Seth RB et al. 2005; Xu LG et al. 2005).
Co-immunoprecipitation assay showed that both TBK1 and IRF3 associated with heat shock protein 90kDa (HSP90), which facilitated signal transduction from TBK1 to IRF3 in Sendai virus (SeV)-infected human embryonic kidney (HEK293) cells (Yang K et l. 2006). MAVS, TBK1 and IRF3 were found to associate with mitochondrial import receptor subunit TOM70 (TOMM70) in HEK293 cells (Liu XY et al. 2010). TOMM70 localizes on the outer membrane of the mitochondria to mediate the translocation of mitochondrial protein precursors from the cytosol into the mitochondria (reviewed in Fan AC & Young JC 2011; Sokol AM et al. 2014; Kreimendahl S & Rassow J 2020). The molecular chaperone complexes of HSP90 and HSP70 were shown to deliver precursor proteins to TOMM70 for subsequent import (Young JC et al. 2003; Zanphorlin LM et al. 2016). The C-terminal motif (EEVD) of HSP90 was found to bind the N-terminal TPR clamp-type domain of TOMM70 (Liu XY et al. 2010; Gava LM et al. 2011). Knockdown of HSP90 by small interfering RNA (siRNA) decreased the association of TOMM70 with TBK1 and IRF3 in HEK293T cells (Liu XY et al. 2010). Further, 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). The data suggest that HSP90 forms a complex with TBK1 and IRF3 in the cytosol and deliver them to the MAVS signalosome on the mitochondria.
Interaction between HSP90 and US11, a viral protein derived from human herpesvirus 1 (HHV-1, also known as herpes simplex virus 1, HSV-1) disrupted the formation of the HSP90:TBK1:IRF3 complex and induced degradation of TBK1 through a proteasome-dependent pathway in mouse embryonic fibroblasts (MEFs) (Liu X et al. 2018).