1. The Two Faces of Receptor Interacting Protein Kinase-1
Ricardo Weinlich, Douglas R. Green 
Molecular Cell 
Volume 56, Issue 4, Pages (November 2014)
DOI: /j.molcel
Copyright © 2014 Elsevier Inc. Terms and Conditions

2. Figure 1 Dual Function of ripk1
Genetics of ripk1 highlight the dual function of this molecule: by promoting organismal lethality, ripk1 is the evil Mr. Hyde; by averting it, ripk1 is the good Dr. Jekyll. Lifespan of mice with different combinations of gene deletions is shown.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2014 Elsevier Inc. Terms and Conditions

3. Figure 2 Antiapoptotic and Proapoptotic Roles of RIPK1
(A) Upon TNFR-1 ligation, RIPK1 stabilizes TNF-R1-induced complex I preventing transition to the proapoptotic complex II. Also, RIPK1 facilitates the activation of the canonical NF-κB pathway, promoting the expression of antiapoptotic molecules, such as FLIP. FLIP inhibits FADD-induced caspase-8 homodimerization in complex II, blocking apoptosis. RIPK1, TAK1, and TAB1 promote, but are not always required for, NF-κB activation in response to TNFR ligation.
(B) In the absence of IAPs, the expression of a kinase-inactive RIPK3 mutant (RIPK3D161N), the addition of a RIPK3 kinase inhibitor, or after enforced RIPK3 dimerization (dimRIPK3) in the absence of MLKL, RIPK1 can promote apoptosis via the recruitment of FADD and caspase-8.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2014 Elsevier Inc. Terms and Conditions

4. Figure 3 Roles of RIPK1 in Necroptosis
(A) Ligation of death receptors or loss of IAPs induce necroptosis by the formation of a complex containing RIPK1, RIPK3, and MLKL under conditions of disruption of the inhibitory complex formed by FADD, Caspase-8, and FLIP.
(B) Enforced dimerization of RIPK1 or its dimerization with RIPK3 can induce necroptosis only when it can seed the formation of RIPK3 oligomers. ΔRHIM indicates that the molecule has a defective RHIM and therefore cannot interact via this motif. dim, dimerization domain.
(C) Different “signal 2s” (e.g., TLR3/4, DAI, and interferons) can induce necroptosis via recruitment of RIPK3 in the absence of RIPK1. RIPK1 blocks necroptosis either through recruitment of the inhibitory complex formed by FADD, caspase-8, and FLIP or when it assumes a kinase-inactive conformation (by the mutation D138N or by Nec-1 inhibition).
Molecular Cell  , DOI: ( /j.molcel )
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5. Figure 4 RIPK1 Function Is Regulated by Ubiquitination
(A) TRAF2, TRAF6, and the E3 ligases cIAP1 and cIAP2 act in concert to add K63-linked ubiquitin chains (K63-Ub) to RIPK1, as does Pel-1. The LUBAC complex, formed by HOIL-1, HOIP, and Sharpin, ubiquitinates RIPK1 with Met-1-linked ubiquitin chains (Met1-Ub). Both modifications stabilize RIPK1 in complex I, activating the NF-κB pathway and inducing the expression of antiapoptotic proteins, such as c-FLIP.
(B) CYLD and OTULIN are deubiquinating enzymes that remove K63-Ub and linear Met1-Ub linkages from RIPK1, respectively, promoting either apoptosis or necroptosis.
(C) RIPK1 modified with K48-linked ubiquitin chains (K48-Ub) is targeted for proteasomal degradation, which sensitizes cells to TNF-induced apoptosis (and possibly signal 2-mediated necroptosis, which is untested). This process is mediated by A20, a ubiquitin-editing enzyme that removes K63-Ub from RIPK1 while adding K48-linked ubiquitin chains, and TRIAD3, a K48-Ub E3 ligase.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2014 Elsevier Inc. Terms and Conditions