RIPK1

Official Full Name

receptor interacting serine/threonine kinase 1

Organism

Homo sapiens

GeneID

8737

Background

This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017]

Synonyms

RIP; RIP1; AIEFL; IMD57; RIP-1;

Bio Chemical Class

Kinase

Protein Sequence

MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEALLEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIILEIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEEDVKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFAPSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPFAQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLDPGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQIGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKNCARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRIDLLSSLIYVSQN

Open

Disease

Alzheimer disease, Cutaneous lupus erythematosus, Malignant haematopoietic neoplasm, Motor neuron disease, Nervous system paraneoplastic/autoimmune disorder, Non-alcoholic fatty liver disease, Pancreatic cancer, Postoperative inflammation, Psoriasis, Rheumatoid arthritis, Ulcerative colitis

Approved Drug

Clinical Trial Drug

9 +

Discontinued Drug

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Detailed Information

The Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) gene is located on human chromosome 6p25.2 and encodes a 671-amino-acid protein belonging to the receptor-interacting protein (RIP) family. RIPK1 consists of an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain, which together form the structural scaffold of the protein. Structurally, the kinase domain exhibits a characteristic bilobal kinase fold, while the death domain adopts a six-helix bundle supersecondary structure, providing a molecular interface for protein-protein interactions. RIPK1 is widely expressed in human tissues, with notable expression in immune cells (such as monocytes, macrophages, and T lymphocytes), neural tissues, and epithelial cells, reflecting its central role in multiple physiological systems.

Gene expression of RIPK1 is positively regulated by the NF-κB signaling pathway, forming a feedback loop essential for cell survival following tumor necrosis factor (TNF) receptor activation. Transcription factors SP1 and EGR1 also contribute to promoter activity regulation. At the post-translational level, RIPK1 undergoes complex modifications, including K63- and M1-linked polyubiquitination, phosphorylation, and proteolytic cleavage. Notably, caspase-8 cleavage at residues D324 and D325 separates the kinase and death domains, limiting pro-apoptotic and pro-necroptotic activity. RIPK1 can also be ubiquitinated by apoptosis inhibitors cIAP1/2, creating a molecular scaffold for NF-κB activation.

Biological Functions and Molecular Mechanisms

RIPK1 functions as a key molecular hub regulating inflammation and cell death in innate immune signaling pathways. Upon TNF binding to its receptor, TNFR1, RIPK1 is recruited to receptor signaling complex I, where it acts as a scaffold. Within complex I, RIPK1 interacts with adaptor proteins such as TRADD, TRAF2/5, and cIAP1/2, promoting K63-linked polyubiquitin chain formation and facilitating IKK complex recruitment, ultimately activating NF-κB. This signaling axis drives transcription of pro-inflammatory cytokines, including IL-6 and TNF-α, as well as anti-apoptotic proteins such as cFLIP and cIAP2, maintaining cell survival and initiating inflammation.

Under deubiquitinated conditions or when cIAPs are inhibited, RIPK1 shifts from pro-survival to pro-death signaling. RIPK1 mediates two parallel cell death pathways through its kinase activity: complex IIa (RIPK1-FADD-caspase-8) drives apoptosis, while complex IIb (RIPK1-RIPK3-MLKL) initiates necroptosis. In apoptosis, RIPK1 activates the caspase-8 cascade, leading to classical apoptotic morphology. In necroptosis, RIPK1 interacts with RIPK3 via the RIP homotypic interaction motif (RHIM) to form amyloid-like structures, activating MLKL membrane pore formation and triggering inflammatory cell death. RIPK1 exhibits dual regulatory roles, inhibiting caspase-8-independent apoptosis and RIPK3-mediated necroptosis under physiological conditions. This function is critical during embryonic development, as RIPK1 knockout mice die shortly after birth with systemic inflammation and excessive intestinal epithelial cell apoptosis. In humans, RIPK1 loss-of-function mutations cause immunodeficiency type 57, characterized by recurrent infections, inflammation, and intestinal ulcers.

Disease Associations and Clinical Significance

Autoinflammatory Diseases

In 2019, an international research team identified heterozygous missense mutations at the RIPK1 caspase-8 cleavage site (p.Asp324Val and p.Asp324His) as the genetic basis of a novel autoinflammatory disorder. Patients from China and Canada presented with recurrent high fevers, lymphadenopathy, and hepatosplenomegaly without overt infections. These mutations impede normal caspase-8 cleavage of RIPK1, resulting in constitutive kinase activation and heightened sensitivity of peripheral blood mononuclear cells (PBMCs) to TNF-induced apoptosis and necroptosis. Patients exhibited elevated serum pro-inflammatory cytokines, including IL-6, TNF-α, IFN-γ, and chemokines, with single-cell RNA sequencing revealing persistent activation of NF-κB and type I interferon pathways, upregulation of IL-8, IL-1B, and CCL3, and increased expression of necroptotic markers RIPK3 and MLKL. Interestingly, compensatory mechanisms varied between cell types; while PBMCs were hyper-inflammatory, dermal fibroblasts showed reduced RIPK1 and TNFR1 expression, increased reduced glutathione, and lower ROS levels, potentially explaining the absence of tissue lesions. Based on the pivotal role of IL-6, patients were treated with the IL-6 receptor inhibitor tocilizumab, which effectively reduced periodic fevers and normalized inflammatory gene expression in PBMCs, exemplifying a precision therapeutic approach.

Figure 1. RIPK1 in TNFR1 signalling. (Mifflin L, et al., 2020)

Emerging Strategies in Cancer Immunotherapy

In 2024, a team at Baylor College of Medicine reported targeting RIPK1 in tumor immunotherapy. RIPK1’s scaffold function contributes to the intrinsic and extrinsic resistance of tumor cells to immune checkpoint blockade (ICB). To overcome the limitations of conventional kinase inhibitors, the researchers developed a PROTAC-based RIPK1 degrader, LD4172, which simultaneously binds RIPK1 and an E3 ubiquitin ligase, promoting ubiquitin-mediated RIPK1 degradation. In preclinical studies, LD4172 selectively degraded RIPK1 both in vitro and in vivo. In B16F10 melanoma and MC38 colon cancer models, LD4172 induced immunogenic cell death, increased tumor-infiltrating CD8+ T cells, and decreased regulatory T cells. When combined with anti-PD-1 therapy, LD4172 restored sensitivity in previously resistant tumors, enhancing dendritic cell activation, IFN-γ+ T-cell infiltration, and secretion of immune-stimulatory cytokines such as IL-2 and IFN-γ. Traditional RIPK1 kinase inhibitors, such as T2I, failed to achieve similar effects, highlighting the advantage of degradation strategies in overcoming scaffold-mediated therapeutic resistance.

Figure 2. RIPK1 Related Development Pipeline

Reference

Degterev A, Ofengeim D, Yuan J. Targeting RIPK1 for the treatment of human diseases. Proc Natl Acad Sci USA. 2019 May 14;116(20):9714-9722.
Mifflin L, Ofengeim D, Yuan J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov. 2020 Aug;19(8):553-571.

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