Posttranslational Modifications in Innate Immunity

Abstract

Taking into account that a large number of nascent gene translation products are subject to limited proteolytic processing, proteolysis is one of the most common PTMs and due to its irreversible nature needs to be very precisely controlled on multiple levels. Since PTMs play a key role in fundamental cellular processes, including the immune response, it is no surprise that these reactions are targets for virulence factors produced by viruses and pathogenic bacteria. By interfering with their host PTM pathways, pathogens disable or hijack for their own benefit host antibacterial mechanisms, manipulate inflammatory reactions, and build up an intracellular or extracellular niche for their survival and proliferation. Significantly, the host targets are mostly limited to several classes of molecules which play a fundamental role in endosome maturation, host cell cytoskeleton remodeling, and the host immune response [1] . In this context it is not surprising that regulatory GTPases are the most common target since they work as central molecular switches of eukaryotic cells regulating cytoskeleton function and membrane trafficking [2] . Alone, Rho and Rab GTPases are modified by adenylylation (AMPylation), ADP-ribosylation, N-acetylo-glucosamination, glucosylation, proteolysis, phosphocholination, transglutamination, deamination, and polyamination by virulence factors produced by a large array of bacterial pathogens [1, 2] . A second most frequently manipulated PTM pathway is kinase signaling involved in The term posttranslational modifications (PTMs) refers to a broad array of versatile chemical alterations of translated proteins. All of these modifications are enzyme catalyzed and allow for fast transformation of protein activity enabling a well-tuned regulation of cell function and response to environmental cues. In this way PTMs add a layer of complexity to gene-encoded protein function, both in prokaryotes and in eukaryotes. PTMs can be reversible or irreversible. Reversible modifications rely on specific enzymatic attachment of simple chemical groups including, for example, phosphate, acetate, methylor hydroxyl-groups, or complex molecules such as lipids, carbohydrates, ADP-ribose, or AMP. Protein phosphorylation catalyzed by kinases, the enzymes transferring a phosphate group from ATP onto the hydroxyl group of serine, threonine, or tyrosine residues in proteins, is the most common PTM. This covalent modification of proteins, often occurring in a cascadelike manner, together with target proteins dephosphorylation by phosphatases, plays a fundamental role in the regulation of numerous signaling pathways in cells. Other common reversible PTMs include the covalent linkage of small proteins, such as ubiquitin and ubiquitin-like proteins (UBLs). On the other hand, enzymatic modification of amino acids, such as deamination of glutamate (transforms Glu into Gln) or deimination of arginine (converts Arg into citrulline), together with proteolytic processing of proteins, represent nonreversible PTMs. Published online: January 27, 2012 Journal of Innate Immunity