Regulation of innate immune responses by suppressor of cytokine signaling (SOCS) proteins

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Innate immunity recognizes conserved microbial structures through their interaction with pattern recognition receptors. Among these, Toll-like receptors (TLR) have been identified to play a crucial role for the activation of innate defense mechanisms. While there is now extensive knowledge as to the signal transduction processes leading to cellular activation upon TLR stimulation, still little is known about subsequent regulatory circuits especially negative-regulation. Shutting down initial TLR activation is absolutely required to limit the potentially detrimental effects of inflammation. Suppressor of cytokine signaling (SOCS) proteins have been identified as inducible feedback inhibitors for JAK/STAT dependent cytokine receptor signaling. Moreover, we and others have shown that SOCS molecules also play an important regulatory role in cells of the innate immune system. To this, SOCS proteins have now been shown also to modulate partial aspects of TLR signaling. However, the precise molecular mechanisms of SOCS in innate immunity are yet to be identified. Moreover, recent work suggests that SOCS might act in a so far unanticipated mode involving the protein modifier ubiquitin and proteasomal degradation. Central goals of this project are: (1) to analyze the molecular modes of action of SOCS proteins, (2) to examine the role of autocrine type I IFN signaling upon TLR triggering and (3) to analyze the role of SOCS as a regulator of infections with intracellular microbes.