Dr. William Kaiser's research program
focuses on the host defense role of programmed cell death (apoptosis and
Our studies demonstrate that programmed necrosis functions as a
critical defense against viral infection; however, dysregulated necroptosis
results in lethal inflammation in mice and understanding this process may
reveal therapeutic strategies to treat chronic inflammatory diseases. Though
once regarding as an unregulated pathological endpoint, necrosis can be
orchestrated by the activity of a protein complex composed of the kinases RIP1
and RIP3. A number of cell stress and host defense pathways prime cells for necroptosis,
and in the context of viral infection, elimination of infected cells benefits
the host. In contrast, dysregulated pronecrotic kinase activity leads to
vasculature defects, collapse in hematopoiesis, and lethal skin and gut
These findings suggest necroptosis may drive a spectrum of
disease states, thus elevating expectations for therapies targeting necrotic
cell death. At present, the pathways
engaged by RIP1/RIP3 to induce necrosis remain incomplete. To define the
molecular basis of necroptosis, we will (1) characterize the signal
transduction pathways upstream and downstream of RIP1/ RIP3, (2) identify new
programmed necrosis signaling components, (3) develop strategies for
therapeutic intervention, and (4) extend these finding to genetic mouse models
of disease caused by excessive cell death.
H, Omoto S, Bertin JS, Gough PJ, Kaiser WJ*â•ª, Mocarski ES*â•ª.
(2015) Herpes Simplex Virus R1 Suppresses Necroptosis. Cell Host & Microbe. 17, 243-251.
MandalP, BergerSB, PillayS, MoriwakiK, HuangC, Guo
H, LichJD, FingerJ, KasparcovaV, VottaB, OuelletteM, KingBW, WisnoskiD, Lakdawala
AS, DeMartinoMP, Casillas LN, HailePA, SehonCA,
MarquisRW, UptonJW, RobackL, RamiaN, DoveyCM,
Carette J, ChanF, BertinJS, GoughPJ, MocarskiES, KaiserWJ. (2014) RIP3 induces apoptosis independent of pro-necrotic kinase activity. Molecular Cell. 56: 481-495.
RickardJA, Anderton H, EtemadiN, Nachbur
U,Darding M, Peltzer N, LalaouiN, LawlorKE,
VanyaiH, HallC, BankovackiA, GangodaL,
WongWW, CorbinJ, HuangC, Mocarski ES,
MurphyJM, AlexanderWS, VossAK, VauxDL,
KaiserWJ, Walczak H, Silke J(2014) TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. eLIFE. 03464.
Kaiser WJâ•ª, Daley-Bauer LP, Thapa RJ, Mandal P, Berger
SB, Huang C, Sundararajan A, Guo H, Roback L, Speck SH, Bertin JS, Gough PJâ•ª,
Balachandran S, Mocarski MSâ•ª. (2014) RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proceedings of the National Academy of
Sciences of the United States of America. 111: 7753-7758.
SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, Capriotti C, Cook M,
Finger J, Hughes-Earle A, Harris PA, Kaiser
WJ, Mocarski ES, Bertin JS, Gough PJ (2014) Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. Journal
of Immunology. 192: 5476-5480.
Upton JU, Kaiser WJ, Mocarski ES.
(2012) DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host & Microbe. 11: 290-297.
Kaiser WJ â•ª, UptonJW, Long AB, Livingston-Rosanoff D, Daley LP, Hakem R,
Caspary T, Mocarski ES. (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 471(7338):
Mocarski ES, Upton JU, Kaiser WJ.
(2011) Viral infection and the evolution of capase-8 regulated apoptotic and necrotic death pathways. Nature Reviews
Immunology. 12: 79-88.
JW*, Kaiser WJ*â•ª, Mocarski ES. (2010) Virus Inhibition of RIP3-dependent Necrosis. Cell Host & Microbe. 7:
* authors contributed equally
â•ª corresponding author