Emerging Principles Governing Signal Transduction by Pattern-Recognition Receptors

The problem of recognizing and disposing of non-self-organisms, whether for nutrients or defense, predates the evolution of multicellularity. Accordingly, the function of the innate immune system is often intimately associated with fundamental aspects of cell biology. Here, we review our current understanding of the links between cell biology and pattern-recognition receptors of the innate immune system. We highlight the importance of receptor localization for the detection of microbes and for the initiation of antimicrobial signaling pathways. We discuss examples that illustrate how pattern-recognition receptors influence, and are influenced by, the general membrane trafficking machinery of mammalian cells. In the future, cell biological analysis likely will rival pure genetic analysis as a tool to uncover fundamental principles that govern host–microbe interactions.The innate immune system uses families of pattern-recognition receptors (PRRs) to recognize diverse microbial ligands (Janeway 1989; Janeway and Medzhitov 2002). During infection, these receptors provide signals that up-regulate general antimicrobial features of the innate immune system as well as instruct and initiate adaptive immunity (Iwasaki and Medzhitov 2010). A significant challenge faced by innate immune recognition is the reliable detection of highly diverse, rapidly evolving microbial organisms, many of which possess virulence mechanisms that enable survival within distinct host niches. Moreover, recognition must be linked to induction of contextual signals appropriate for the type of infection. The specificity, signal transduction, and cell biology of PRRs have evolved under these selective pressures to enable broad recognition of microbes within each host niche.Although the collection of PRRs is decidedly less diverse than antigen receptors of the adaptive immune system, the list of players has grown considerably over the past decade (Kawai and Akira 2010). If one classifies these receptors based on common structure and functional domains, then six families emerge: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), AIM-like receptors (ALRs), Nod-like receptors (NLRs), and OAS-like receptors (OLRs) (Geijtenbeek and Gringhuis 2009; Kawai and Akira 2010; Rathinam and Fitzgerald 2011; Lamkanfi and Dixit 2012; Kranzusch et al. 2013). Collectively, these receptors bind a diverse array of targets, including lipoproteins, polysaccharides, nucleic acids, carbohydrate structures, and a few highly conserved microbial proteins. These ligands are typically shared across large microbial classes, which facilitate broad recognition with such a limited number of PRRs. Moreover, alteration or masking of these ligands to avoid PRR activation often results in reduced microbial fitness.The molecular recognition challenge faced by PRRs is all the more complex when one considers the need to detect microbes within distinct subcellular niches. Microbes can be extracellular or intracellular within membrane-bound organelles, within the cytosol, or in the nucleus. In addition, both the innate and adaptive immune mechanisms appropriate for eliminating microbes within these distinct environments are quite distinct, so it is vital that PRR signaling communicate the location of a microbe as well its nature. We now understand that members of the PRR families highlighted above localize to distinct subcellular compartments, and, in some cases, localization can change in a dynamic fashion that regulates or influences recognition and signaling. Moreover, in some cases, signal transduction and resulting gene induction can be dramatically influenced by the organelle from which signaling initiates. Thus, the innate immune system has harnessed the organization inherent to cells as a means of achieving regulation and signaling specificity. Activation of PRRs can also feed back on basic cell biological processes, such as phagocytosis and autophagy, to enhance or accelerate the response to microbial infection.In the following sections, we discuss these links between cell biology and PRRs of mammalian innate immunity. Our discussions of PRR function and signal transduction will be limited to this theme, as a result, in part, of space constraints but also because in-depth reviews of each PRR family have appeared elsewhere. For discussion purposes, we have grouped the transmembrane PRRs together and the cytosolic PRRs together.