Posttranslational Modification as a Critical Determinant of Cytoplasmic Innate Immune Recognition

• Published in: Physiological reviews Vol. 97; no. 3; pp. 1165 - 1209
• Main Authors: Baker, Paul J, De Nardo, Dominic, Moghaddas, Fiona, Tran, Le Son, Bachem, Annabell, Nguyen, Tan, Hayman, Thomas, Tye, Hazel, Vince, James E, Bedoui, Sammy, Ferrero, Richard L, Masters, Seth L
• Format: Journal Article
• Language: English
• Published: United States 01.07.2017
• Subjects: Animals; Cytoplasm - immunology; Cytoplasm - metabolism; Epitopes; Humans; Immunity, Innate; Protein Processing, Post-Translational - immunology; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; Signal Transduction
• ISSN: 0031-9333; 1522-1210
• DOI: 10.1152/physrev.00026.2016

Cell surface innate immune receptors can directly detect a variety of extracellular pathogens to which cytoplasmic innate immune sensors are rarely exposed. Instead, within the cytoplasm, the environment is rife with cellular machinery and signaling pathways that are indirectly perturbed by pathogenic microbes to activate intracellular sensors, such as pyrin, NLRP1, NLRP3, or NLRC4. Therefore, subtle changes in key intracellular processes such as phosphorylation, ubiquitination, and other pathways leading to posttranslational protein modification are key determinants of innate immune recognition in the cytoplasm. This concept is critical to establish the "guard hypothesis" whereby otherwise homeostatic pathways that keep innate immune sensors at bay are released in response to alterations in their posttranslational modification status. Originally identified in plants, evidence that a similar guardlike mechanism exists in humans has recently been identified, whereby a mutation that prevents phosphorylation of the innate immune sensor pyrin triggers a dominantly inherited autoinflammatory disease. It is also noteworthy that even when a cytoplasmic innate immune sensor has a direct ligand, such as bacterial peptidoglycan (NOD1 or NOD2), RNA (RIG-I or MDA5), or DNA (cGAS or IFI16), it can still be influenced by posttranslational modification to dramatically alter its response. Therefore, due to their existence in the cytoplasmic milieu, posttranslational modification is a key determinant of intracellular innate immune receptor functionality.