Abstract
The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response.
Highlights
Transcription factor Nuclear factor (NF)-kB activates the expression of numerous target genes, most of which are involved in regulating innate and adaptive immune responses [1,2]
Inflammatory cytokine production depends on transcription factor NFkB, whose activity is controlled by a kinase complex that includes the NF-kB essential modulator (NEMO)
In this study we identify a highly effective viral strategy to blunt the host inflammatory response: The murine cytomegalovirus M45 protein binds to NEMO and redirects it to autophagosomes, vesicular structures that deliver cytoplasmic constituents to lysosomes for degradation and recycling
Summary
Transcription factor NF-kB activates the expression of numerous target genes, most of which are involved in regulating innate and adaptive immune responses [1,2]. It is activated in response to a variety of stimuli, which include pathogen-associated molecular patterns (PAMPs) and proinflammatory cytokines, such as TNFa and IL-1b. The best characterized PRRs are the TLRs, a family of transmembrane proteins that recognize PAMPs at the cell surface or within endosomes [4]. They detect a broad range of PAMPs originating from viruses, bacteria or fungi. TLR2 and 4 are typically activated by bacterial peptidoglycans and lipopolysacharide (LPS), respectively. They can be activated by certain viral glycoproteins [5]. Other TLRs, such as TLR3, 7, and 9, recognize double- or single-stranded RNA or unmethylated DNA of viral or bacterial origin [6]
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