title: Cloaked in ubiquitin, a killer hides in plain sight: the molecular regulation of RIPK1.
abstract: In the past decade, studies have shown how instrumental programmed cell death (PCD) can be in innate and adaptive immune responses. PCD can be a means to maintain homeostasis, prevent or promote microbial pathogenesis, and drive autoimmune disease and inflammation. The molecular machinery regulating these cell death programs has been examined in detail, although there is still much to be explored. A master regulator of programmed cell death and innate immunity is receptor-interacting protein kinase 1 (RIPK1), which has been implicated in orchestrating various pathologies via the induction of apoptosis, necroptosis, and nuclear factor-κB-driven inflammation. These and other roles for RIPK1 have been reviewed elsewhere. In a reflection of the ability of tumor necrosis factor (TNF) to induce either survival or death response, this molecule in the TNF pathway can transduce either a survival or a death signal. The intrinsic killing capacity of RIPK1 is usually kept in check by the chains of ubiquitin, enabling it to serve in a prosurvival capacity. In this review, the intricate regulatory mechanisms responsible for restraining RIPK1 from killing are discussed primarily in the context of the TNF signaling pathway and how, when these mechanisms are disrupted, RIPK1 is free to unveil its program of cellular demise.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, New York, NY, USA.|Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Justus
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, New York, NY, USA.
authors.forename: Adrian T
authors.initials: AT
authors.lastname: Ting
mesh_terms: D000818:Animals; D017209:Apoptosis; D006801:Humans; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: CYLD; Caspase-8; RIPK1; RIPK3; apoptosis; necroptosis; ubiquitin