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Targeting RIPK1 for the Treatment of Human Diseases INAUGURAL ARTICLE Targeting RIPK1 for the treatment of human diseases INAUGURAL ARTICLE Alexei Degtereva,1, Dimitry Ofengeimb,1, and Junying Yuanc,2 aDepartment of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02445; bRare and Neurologic Disease Research Therapeutic Area, Sanofi US, Framingham, MA 01701; and cDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2017. Edited by Don W. Cleveland, University of California, San Diego, La Jolla, CA, and approved April 8, 2019 (received for review January 21, 2019) RIPK1 kinase has emerged as a promising therapeutic target for carrying different RIPK1 kinase dead knock-in mutations, including the treatment of a wide range of human neurodegenerative, D138N, K45A, K584R, and ΔG26F27,aswellasRIPK3orMLKL autoimmune, and inflammatory diseases. This was supported by knockout mutations, show no abnormality in development or in the extensive studies which demonstrated that RIPK1 is a key mediator adult animals (6–10). Thus, necroptosis might be predominantly of apoptotic and necrotic cell death as well as inflammatory path- activated under pathological conditions, which makes inhibiting ways. Furthermore, human genetic evidence has linked the dysre- this pathway an attractive option for the treatment of chronic gulation of RIPK1 to the pathogenesis of ALS as well as other human diseases. inflammatory and neurodegenerative diseases. Importantly, unique Necroptosis was first defined by a series of small-molecule allosteric small-molecule inhibitors of RIPK1 that offer high selectivity inhibitors (necrostatins), including Nec-1/Nec-1s, Nec-3, Nec-4, have been developed. These molecules can penetrate the blood–brain and Nec-5, which blocked TNF-α–induced necrotic cell death barrier, thus offering the possibility to target neuroinflammation and (11). Subsequent studies of necrostatins revealed a key role of cell death which drive various neurologic conditions including Alz- RIPK1 as an important pharmacological target for inhibiting heimer’s disease, ALS, and multiple sclerosis as well as acute neuro- necroptosis (12). Importantly, the kinase activity of RIPK1 plays logical diseases such as stroke and traumatic brain injuries. We discuss a central role in mediating multiple deleterious inflammatory the current understanding of RIPK1 regulatory mechanisms and cell death mechanisms upon the activation of TNFR1 by TNF-α, emerging evidence for the pathological roles of RIPK1 in human dis- which is known to be involved in the pathogenesis of various eases, especially in the context of the central nervous systems. human diseases (13). Anti-TNF agents have achieved major CELL BIOLOGY clinical success for the treatment of human inflammatory dis- RIPK1 | necroptosis | apoptosis | inflammation | neurodegeneration eases in the periphery, such as rheumatoid arthritis, colitis, and psoriasis. However, anti-TNF strategy is not safe for the treat- ell death is a fundamental process that controls organismal ment of CNS diseases due to the involvement of TNFR2 in Cdevelopment and homeostasis by regulating cell numbers mediating neural regeneration (14). The specificity of RIPK1 in and eliminating damaged or infected cells. The discovery of mediating TNFR1 signaling provides the possibility to safely apoptosis as a regulated cell death mechanism suggested the ameliorate the deleterious TNF responses in the CNS without possibility of developing therapeutics to block pathologic cell affecting TNFR2. death, common in human degenerative diseases. Caspases, a RIPK1 has become an important drug target in the pharma- family of homologous mammalian cysteine proteases that are key ceutical industry not only due to its key roles in TNF signaling mediators of apoptosis, emerged as attractive targets in pre- responses but also because the kinase structure of RIPK1 is venting pathologic cell death (1). A major drug discovery effort highly amenable for developing specific pharmacological small- targeting caspases ensued in the mid-1990s (2). However, these molecule inhibitors. Nec-1/Nec-1s have been widely used to de- efforts largely failed to deliver new therapies. The reasons for fine the role of necroptosis and RIPK1 in human diseases using this failure include the presence of multiple members of caspases animal models. This included studies examining the role of this with somewhat redundant functions, the involvement of caspases kinase in both acute injuries like ischemia as well as chronic in important physiological functions, the activation of alternative neurodegenerative conditions such as multiple sclerosis (MS), cell death mechanisms upon inhibition of apoptosis and intrinsic ALS, and Alzheimer’s disease (AD) (13, 15, 16). To date, two toxicity-related challenges in inhibiting this class of cysteine proteases. As a result, it remained unclear whether blocking cell Significance death could be an effective strategy for the treatment of de- generative and inflammatory human diseases. RIPK1 plays a critical role in mediating deleterious responses Unexpectedly, apoptosis is not the only contributor to pa- downstream of TNFR1. RIPK1 inhibitors have been progressed thology in human diseases; other forms of regulated cell death successfully past human phase I clinical studies. This paper also play critical roles. In particular, necrosis, defined morpho- discusses why RIPK1 inhibitors present an opportunity for de- logically by cell lysis with the release of intracellular contents into veloping oral drugs for a range of human degenerative and the extracellular space and traditionally believed to represent inflammatory diseases, especially CNS pathologies, including passive cell death, has attracted significant attention. Necrosis ALS, Alzheimer’s disease, Parkinson’s disease, traumatic brain can be induced by diverse events that disrupt normal cellular injury, stroke, and lysosomal storage diseases. physiological processes. However, a key question emerged whether there may also be a dedicated regulated mechanism that mediates Author contributions: A.D., D.O., and J.Y. wrote the paper. the execution of necrosis, similar to that of caspases in mediating Conflict of interest statement: J.Y. is a consultant for Denali Therapeutics. D.O. is an apoptosis. The first established example of such a pathway is nec- employee of Sanofi. roptosis, a regulated necrotic cell death mechanism that can be This article is a PNAS Direct Submission. activated under apoptosis-deficient conditions and is controlled by This open access article is distributed under Creative Commons Attribution-NonCommercial- the kinase activity of RIPK1 and its downstream mediators: NoDerivatives License 4.0 (CC BY-NC-ND). RIPK3 kinase and the pseudokinase MLKL (3, 4). Interestingly, 1A.D. and D.O. contributed equally to this work. while mice carrying mutations in different caspases display signifi- 2To whom correspondence should be addressed. Email: [email protected]. cant developmental defects (5), necroptosis-resistant mutant mice www.pnas.org/cgi/doi/10.1073/pnas.1901179116 PNAS Latest Articles | 1of9 Downloaded by guest on September 27, 2021 different RIPK1 kinase inhibitor programs have progressed through (IKK) through a polyubuiquitin-binding adaptor subunit IKKγ/ human phase I safety trials. NEMO (15, 17). The activation of RIPK1 is inhibited by direct phosphorylation by TAK1, IKKα/β, MK2, and TBK1 (13). Regulation of Necroptosis by RIPK1 Kinase in Response to cIAP1 was also found to mediate K48 ubiquitination of RIPK1, α TNF- inhibiting its catalytic activity and promoting degradation (19). RIPK1 is a multidomain protein comprising an N-terminal ki- When cells are defective in activating the apical apoptotic nase domain, an intermediate domain, and a C-terminal death mediator caspase-8, TNF-α stimulation promotes activation of a domain (DD). The intermediate domain of RIPK1 contains an secondary cytosolic amyloid-like “necrosome” complex, also RHIM [receptor interacting protein (rip) homotypic interaction known as Complex IIb. This complex contains a hetero-oligomer motif] domain which is important for interacting with other of RIPK1 and RIPK3 which interact through their cognate RHIM-containing proteins such as RIPK3, TRIF, and ZBP1. RHIM domains (20). The activation of RIPK1 kinase precedes The C-terminal DD mediates its recruitment by interacting with and is essential for the formation of the necrosome. Activated other DD-containing proteins, such as TNFR1 and FADD, and RIPK1 undergoes autophosphorylation on multiple residues in- its homodimerization to promote the activation of the N- cluding Ser14/15, Ser20, and Ser161/166 in the activation seg- terminal kinase domain (10). In the case of TNF-α signaling, ment (12). Ser166 phosphorylation has emerged as a biomarker ligand-induced TNFR1 trimerization leads to the assembly of a for RIPK1 activation (12, 21, 22). RIPK3 is phosphorylated in large receptor-bound signaling complex, termed Complex I, which includes multiple adaptors (TRADD, TRAF2, and necrosomes on Ser227, and RIPK3 homo-oligomers eventually RIPK1), and E3 ubiquitin ligases (cIAP1/2, LUBAC complex) phosphorylate MLKL on the activation segment residues Thr357/ (15, 17) (Fig. 1). Ser358 (23). The ensuing conformational change in MLKL leads RIPK1 is regulated by multiple posttranslational modifica- to the formation of disulfide
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