Abstract
During early infection, viruses activate cellular stress-response proteins such as heat-shock proteins (Hsps) to counteract apoptosis, but later on, they modulate these proteins to stimulate apoptosis for efficient viral dissemination. Hsp70 has been attributed to modulate viral entry, transcription, nuclear translocation and virion formation. It also exerts its anti-apoptotic function by binding to apoptosis protease-activating factor 1 (Apaf-1) and disrupting apoptosome formation. Here, we show that influenza A virus can regulate the anti-apoptotic function of Hsp70 through viral protein M1 (matrix 1). M1 itself did not induce apoptosis, but enhanced the effects of apoptotic inducers. M1-small-interfering RNA inhibits virus-induced apoptosis in cells after either virus infection or overexpression of the M1 protein. M1 binds to Hsp70, which results in reduced interaction between Hsp70 and Apaf-1. In a cell-free system, the M1 protein mediates procaspase-9 activation induced by cytochrome c/deoxyadenosine triphosphate. A study involving deletion mutants confirmed the role of the C-terminus substrate-binding domain (EEVD) of Hsp70 and amino acids 128–165 of M1 for this association. The M1 mutants, which did not co-immunoprecipitate with Hsp70, failed to induce apoptosis. Overall, the study confirms the proapoptotic function of the M1 protein during influenza virus infection.
Highlights
heat-shock proteins (Hsps) mainly function as cellular chaperones to maintain protein folding and renaturation.[7]
Cleavage of caspases into their proteolytically active subunits was further confirmed by immunoblotting in which higher levels of cleavage products of caspase-9 (p37/p35) and caspase-3 (p20/p17) were observed in only PR8 virus-infected cells but not in M1-small-interfering RNA (siRNA)- and virus-infected cells (Figure 1c)
The results suggested the role of the M1 protein during virus-induced apoptosis, it could not be ascertained whether the M1 protein alone is an apoptotic factor or whether it exerts its function in cooperation with other influenza virus proteins
Summary
Hsps mainly function as cellular chaperones to maintain protein folding and renaturation.[7]. The M1 of influenza A virus is a phosphorylated 252 aminoacid (aa), major structural protein, which tightly associates with ribonucleoprotein cores while interacting with the membrane envelope and the cytoplasmic tails of spike glycoprotein.[25] The M1 protein has been shown to directly bind to heat-shock cognate protein 70 (Hsc70).[26] As Hsp[70] is the structural homolog of Hsc[70] and has been shown to modulate caspase-9 activation,[13,14,15,27,28] a possible interaction of M1 with Hsp[70] was hypothesized. The study confirms that binding of the M1 protein to Hsp[70] disrupts the Hsp70– Apaf-1 complex, resulting in formation of functional apoptosome and activation of caspase-9. The results emphasize the significant role of virus-encoded proteins in modulating cellular proteins for exploiting the cellular defense machinery to their benefit
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