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RIP1 Suppresses Innate Immune Necrotic As Well As Apoptotic Cell Death During Mammalian Parturition

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RIP1 Suppresses Innate Immune Necrotic As Well As Apoptotic Cell Death During Mammalian Parturition RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition William J. Kaisera,1, Lisa P. Daley-Bauera, Roshan J. Thapab, Pratyusha Mandala, Scott B. Bergerc, Chunzi Huanga, Aarthi Sundararajana, Hongyan Guoa, Linda Robacka, Samuel H. Specka, John Bertinc, Peter J. Goughc,1, Siddharth Balachandranb, and Edward S. Mocarskia,1 aDepartment of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; bImmune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and cPattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426 Edited by Michael Karin, University of California, San Diego School of Medicine, La Jolla, CA, and approved April 16, 2014 (received for review February 27, 2014) The pronecrotic kinase, receptor interacting protein (RIP1, also called architecture facilitates convergent death domain-dependent and RIPK1) mediates programmed necrosis and, together with its partner, RHIM-dependent pathways. RIP1 partners with death domain- RIP3 (RIPK3), drives midgestational death of caspase 8 (Casp8)-deficient containing proteins, particularly fas-associated death domain pro- embryos. RIP1 controls a second vital step in mammalian development tein (FADD), as well as RHIM-containing proteins, such as the immediately after birth, the mechanism of which remains unresolved. pronecrotic kinase RIP3 and the TLR3/TLR4 adapter TIR- −/− Rip1 mice display perinatal lethality, accompanied by gross immune domain–containing adapter-inducing IFN (TRIF) (8, 9). RIP1 is system abnormalities. Here we show that RIP1 K45A (kinase dead) essential for TNF-induced necroptosis but dispensable for other knockin mice develop normally into adulthood, indicating that devel- forms of RIP3 kinase-dependent death (10, 11). Oligomerization of opment does not require RIP1 kinase activity. In the face of complete RIP1 through either domain promotes activation of its N-terminal RIP1 deficiency, cells develop sensitivity to RIP3-mixed lineage kinase serine/threonine kinase and triggers either of two distinct cell death domain-like–mediated necroptosis as well as to Casp8-mediated apo- pathways: (i) apoptosis following assembly of a cytosolic FADD– ptosis activated by diverseinnateimmunestimuli(e.g.,TNF,IFN,dou- Casp8–cellular FLICE-like inhibitory protein (cFLIP)-containing ble-stranded RNA). When either RIP3 or Casp8 is disrupted in complex or (ii) necroptosis via RIP3-dependent, mixed lineage kinase IMMUNOLOGY combination with RIP1, the resulting double knockout mice exhibit domain-like (MLKL)-mediated membrane permeabilization (1–4). slightly prolonged survival over RIP1-deficient animals. Surprisingly, In addition to death, RIP1 activation downstream of either triple knockout mice with combined RIP1, RIP3, and Casp8 deficiency TNFR1 or TNFR2 facilitates prosurvival NF-κB gene expression develop into viable and fertile adults, with the capacity to produce contingent on the balance of ubiquitination and deubiquitination normal levels of myeloid and lymphoid lineage cells. Despite the com- (12). In this context, deubiquitination converts RIP1 into bined deficiency, these mice sustain a functional immune system that a death-inducing adapter within the TNFR-signaling complex Rip3 responds robustly to viral challenge. A single allele of is tolerated (12). RIP1 remains a component of a death receptor-free cyto- Rip1−/−Casp8−/−Rip3+/− in mice, contrasting the need to eliminate solic complex, termed complex II (also called the ripoptosome) Rip1 Rip3 both alleles of either or to rescue midgestational death (1–3), together with FADD, Casp8, and cFLIP where cFLIP Casp8 of -deficient mice. These observations reveal a vital kinase- levels control Casp8 activation (13) and death (14). When Casp8 independent role for RIP1 in preventing pronecrotic as well as or FADD are absent or Casp8 activity is inhibited (14–17), RIP1 proapoptotic signaling events associated with life-threatening in- nate immune activation at the time of mammalian parturition. Significance interferon | MLKL | herpesvirus The protein kinase receptor interacting protein 1 controls sig- naling via death receptors, Toll-like receptors, and retinoic acid- eceptor interacting protein (RIP) kinase RIP1 (RIPK1) func- inducible gene 1-like receptors, dictating inflammatory out- Rtions as an essential adapter in a number of innate immune comes as broad as cytokine activation and cell death. RIP1 signal transduction pathways, including those initiated by Toll-like makes a vital contribution during development, evident from receptor (TLR)3, TLR4, and retinoic acid-inducible gene 1 (RIG- – the fact that RIP1-deficient mice die soon after birth. Here, we I)-like receptors, in addition to death receptors (1 4). Signaling via show that a kinase-independent function of RIP1 dampens the these pathways bifurcates at the level of RIP1 to produce opposing consequences of innate immune cell death. During parturition, outcomes, a prosurvival inflammatory response counterbalanced by RIP1 prevents the lethal consequences of RIP3-dependent nec- extrinsic cell death signaling that drives either apoptosis or nec- roptosis as well as caspase 8 (Casp8)-dependent apoptosis. In roptosis. Despite the normal development of many organs and contrast to the RIP1-deficient phenotype, mice lacking a com- neuromuscular architecture, RIP1-null mice die within a few days of bination of RIP1, RIP3, and Casp8 are born and mature into birth with signs of edema as well as significant levels of cell death viable, fertile, and immunocompetent adults. These results within lymphoid tissues, particularly immature thymocytes (5). Al- demonstrate the important protective role of RIP1 against though TNF-signaling contributes to this perinatal death (6) and physiologic and microbial death cues encountered at birth. implicates the prosurvival role of RIP1 in activating nuclear factor κB(NF-κB) (5), the precise mechanism responsible for de- Author contributions: W.J.K., L.P.D.-B., R.J.T., and S.B. designed research; W.J.K., L.P.D.-B., velopmental failure of RIP1-deficient mice remains unresolved. It R.J.T., P.M., C.H., A.S., H.G., and L.R. performed research; S.B.B., J.B., and P.J.G. contrib- uted new reagents/analytic tools; W.J.K., L.P.D.-B., R.J.T., P.M., S.H.S., S.B., and E.S.M. seems likely that dysregulation of additional signaling pathways analyzed data; and W.J.K., S.B., and E.S.M. wrote the paper. contributes to this phenotype, given that deficiency in TNF receptor Conflict of interest statement: P.J.G., J.B., and S.B.B. are employees of GlaxoSmithKline. 1 (TNFR1) only modestly extends the lifespan of RIP1-null mice This article is a PNAS Direct Submission. and deficiency in TNFR2 only rescues thymocytes from death (7). 1To whom correspondence may be addressed. E-mail: [email protected], peter.j.gough@ RIP1 orchestrates assembly of distinct signaling platforms via two gsk.com, or [email protected]. – C-terminal protein protein binding domains: a death domain and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. a RIP homotypic interaction motif (RHIM) (3, 4). This unique 1073/pnas.1401857111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1401857111 PNAS | May 27, 2014 | vol. 111 | no. 21 | 7753–7758 Downloaded by guest on October 3, 2021 mediates RHIM-dependent recruitment of RIP3. Then, RIP1 AB C kinase activity facilitates RIP3 kinase-dependent phosphoryla- RIP1-/- tion of MLKL to drive necroptosis (18, 19). Importantly, basal RIP1 KD/KD WT Casp8 activity conferred by cFLIP blocks this process (14), and 125 RIP1 KD/KD WT RIP1 KD/KD in vivo, this translates into a unique requirement for Casp8 to 100 RIP1 prevent RIP3-dependent embryonic lethality and tissue inflam- 75 – RIP3 mation triggered by Casp8 or FADD compromise (14 17). Re- 50 cently, the importance of Casp8 suppression of necroptosis has been extended to diverse innate signaling pathways, including 25 β-actin Percent survival 0 those activated by TLR3 as well as type I or II interferon (IFN) % untreated cells Viability MEFs (11, 20, 21), broadening a concept that first emerged in death 0 71 52 TNF+BV6 TNF+CHX receptor signaling (3, 4). Once TLR3 becomes activated, the Time (weeks) adapter protein TRIF recruits RIP1 or RIP3 via RHIM inter- TNF+zVAD+BV6 TNF+zVAD+BV6+Nec1 actions (8). In this context, the RIP1 death domain ensures the TNF+zVAD+BV6+GSK’872 suppression of necrotic death by recruiting FADD, Casp8, and cFLIP. Necroptosis is unleashed whenever Casp8 or FADD is Rip1+/-Casp8+/- intercross D WT E Mendelian Observed compromised. Likewise, IFN activation of protein kinase R sets RIP1-/- frequency frequency No.of mice Died prior to – – – RIP1 KD/KD Genotype (%) (%) weaned weaning up a similar relationship with the FADD Casp8 cFLIP RIP1 +/+ +/+ RIP1-/-Casp8-/- Rip1 Casp8 6.3 13.4 15 +/- +/+ complex (21). Thus, innate immunity elicits dueling signals that 125 Rip1 Casp8 12.5 17 19 both potentiate and suppress programmed necrosis. 100 Rip1-/-Casp8+/+ 6.3 0 0 P2-P3 In this study, we implicate multiple innate immune signaling Rip1+/+ Casp8+/- 12.5 30.4 34 75 pathways in the death of RIP1-deficient mice. Once dysregulated Rip1+/-Casp8+/- 25 39.3 44 -/- +/- by disruption of RIP1, RIP3-mediated necroptosis and Casp8- 50 Rip1 Casp8 12.5 0 0* P2-P3 Rip1+/+ Casp8-/- # 25 6.3 0 0 E10.5 dependent apoptosis contribute to death at the time of birth. Rip1+/-Casp8-/- 12.5 0 0# E10.5 0 Rip1-/-Casp8-/- Our observations bring to light the consequences of diverse in- % untreated cells Viability 6.3 0 0* P5-P16 TNF * denotes perinatal lethal nate immune stimuli arising from TNF, IFN, and/or nucleic acids # denotes embryonic lethal Total 112 that play out during mammalian parturition. RIP1 plays a vital TNF+zVAD KD/KD −/− −/− role suppressing cell death consequences of this innate signaling. Fig. 1. Survival of Rip1 but not Rip1 Casp8 mice implicates pro- −/− RIP3 and Casp8 must be eliminated to rescue RIP1-null mice grammed necrosis in perinatal death of Rip1 mice.
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