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Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death

Nature Reviews Molecular Cell Biology volume 14, pages 727–736 (2013)Cite this article

Subjects

Key Points

  • Receptor-interacting protein 1 (RIP1) contains an amino-terminal kinase domain, a carboxy-terminal death domain and an intermediate domain with a receptor-interacting protein homotypic interaction motif (RHIM).

  • RIP1 has emerged as a key upstream regulator that controls inflammatory signalling as well as the activation of multiple cell death pathways, including apoptosis and necroptosis.

  • The ability of RIP1 to modulate these key cellular events is tightly controlled by ubiquitylation, deubiquitylation and the interaction of RIP1 with a class of ubiquitin receptors.

  • Ubiquitylation of RIP1 might provide a unique 'ubiquitin code' that determines whether a cell activates cell survival through the nuclear factor-κB (NF-κB)-dependent or -independent pathways or induces cell death through necroptosis or apoptosis.

  • Targeting RIP1 kinase might provide novel therapeutics for the treatment of both acute and chronic human diseases.

Abstract

Receptor-interacting protein 1 (RIP1) kinase has emerged as a key upstream regulator that controls inflammatory signalling as well as the activation of multiple cell death pathways, including apoptosis and necroptosis. The ability of RIP1 to modulate these key cellular events is tightly controlled by ubiquitylation, deubiquitylation and the interaction of RIP1 with a class of ubiquitin receptors. The modification of RIP1 may thus provide a unique 'ubiquitin code' that determines whether a cell activates nuclear factor-κB (NF-κB) to promote inflammatory signalling or induces cell death by apoptosis or necroptosis. Targeting RIP1 might be a novel therapeutic strategy for the treatment of both acute and chronic human diseases.

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Figure 1: RIP1-mediated multimodal signalling events downstream of TNFR1.
Figure 2: The domains and post-translational modifications of RIP1.
Figure 3: The involvement of RIP1 in TLR4 signalling.
Figure 4: The caspase 8 cleavage site at Asp324 of RIP1 in the intermediate domain.

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Acknowledgements

The authors thank the members of the Yuan laboratory for stimulating discussions. Work in the authors' laboratory was supported in part by a Merit Award from the National Institute on Aging and a Senior Fellowship from the Ellison Foundation (to J.Y.). D.O. was supported in part by the Molecular Biology of Neurodegeneration Training Grant from the National Institute of Neurological Disorders and Stroke (Principle Investigator B. Yankner) and a fellowship from the MS Society.

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  1. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Dimitry Ofengeim & Junying Yuan

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Correspondence to Junying Yuan.

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Glossary

Toll-like receptor

(TLR). A family of single membrane-spanning receptors that can be activated by structurally conserved molecules derived from microorganisms. They have a key role in innate immunity.

Necroptosis

A caspase-independent necrotic cell death pathway that is controlled by receptor-interacting protein 1 (RIP1) kinase and its downstream mediator RIP3 kinase.

Apoptosis

An evolutionarily conserved cell death mechanism that is executed by caspases.

Death receptor

A family of single membrane-spanning receptors that are characterized by an intracellular death domain. They have a role in mediating inflammation and cell death.

Complex I

The protein complex that is formed at the intracellular death domain of TNF receptor 1 (TNFR1) upon stimulation by tumour necrosis factor (TNF). This complex includes TNFR1-associated death domain protein (TRADD), receptor-interacting protein 1 (RIP1), TNFR-associated factor 2 (TRAF2) and/or TRAF5, as well as cellular inhibitor of apoptosis protein 1 (cIAP1) and/or cIAP2.

Inflammasome

A protein complex that is involved in mediating caspase 1 activation and interleukin-1 (IL-1) processing during inflammation.

Necrostatin 1

A highly specific small-molecule inhibitor of receptor-interacting protein 1 (RIP1) kinase. 7-Cl-O-Nec-1 (5-(7-chloro-1H-indol-3-yl)methyl)-3-methylimidazolidine-2,4-dione) is an improved analogue of necrostatin 1. This analogue binds to RIP1 kinase with high affinity (with a dissociation constant (Kd) of ∼3 nM) and is suitable for in vivo use in animal models.

Complex IIb

A cytosolic complex that includes receptor-interacting protein 1 (RIP1) and RIP3. This complex is formed downstream of complex I upon the activation of TNF receptor 1 (TNFR1) by tumour necrosis factor (TNF) to mediate necroptosis.

Complex IIa

A cytosolic complex comprising receptor- interacting protein 1 (RIP1), FAS-associated death domain protein (FADD) and caspase 8. This complex is formed downstream of complex I upon the activation of TNF receptor 1 (TNFR1) by tumour necrosis factor (TNF) to mediate apoptosis.

Chronic proliferative dermatitis mutation mice

(cpdm mice). CPD is a spontaneous mutation in C57BL/Ka mice (cpdm/cpdm). The dermatitis is characterized by redness, hair loss, scaling and pruritus and histologically by epithelial hyperproliferation and infiltration of eosinophils, macrophages and mast cells.

Paneth cells

A type of intestinal epithelial cell identified microscopically by their location just below the intestinal stem cells in the intestines. They have important functions in the maintenance of the gastrointestinal barrier.

Goblet cells

A type of intestinal epithelial cell that secretes mucin, which dissolves in water to form mucus. They are important to preserve the integrity of the intestine.

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Ofengeim, D., Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 14, 727–736 (2013). https://doi.org/10.1038/nrm3683

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