Role of non-degradative ubiquitination in interleukin-1 and toll-like receptor signaling.

Introduction The induction of an appropriate immune response upon infection of an invading pathogen is controlled by host pattern recognition receptors (PRRs)* that specifically recognise essential structural components of infectious agents termed pathogen-associated molecular patterns (PAMPs) (1-3). Detection of PAMPs by PRRs triggers intracellular signalling pathways leading to the expression of immune mediators such as cytokines, chemokines and type I interferons (IFNs). Toll-like receptors (TLRs) represent a now well-defined PRR family, since much has been discovered recently in terms of the PAMPs they interact with, the downstream signalling pathways triggered and the complex yet specific immune responses elicited. TLRs are expressed on both immune and non-immune cells (1), and are part of the interleukin-1 (IL-1) receptor/TLR superfamily, a family of proteins defined by the presence of a common cytoplasmic signalling domain (the Toll-IL-1 receptor (TIR) domain) which also includes the IL-1, IL-18 and IL-33 receptors (4). The TLRs can be divided into two subgroups based on their subcellular location: one comprising TLR1, TLR2, TLR4, TLR5 and TLR6 which signal from the plasma membrane and a second containing TLR3, TLR7, TLR8 and TLR9 which are localised to endosomal compartments. TLR2 functions as a heterodimer with either TLR1 or TLR6 to respond to either bacterial triacyl or diacyl lipopeptides, respectively. TLR4 forms homodimers in response to lipopolysaccharide (LPS) from Gram-negative bacteria. TLR3 binds viral dsRNA, while TLR7 and 8 detect viral ssRNA.