Andrew Oberst, Ph.D.

Andrew Oberst, Ph.D.

Assistant Professor, Immunology

Dr. Andrew Oberst graduated from Amherst College in 2001, and pursued his graduate studies in Europe, in a collaborative program between the Universities of Rome and Paris. He received his Doctorate in 2006, then completed postdoctoral training at St. Jude Children’s Research Hospital in Memphis, TN. He joined the Department of Immunology as an Assistant Professor in 2012.

Contact Info

Department of Immunology
University of Washington
Office E306, Box 358059
750 Republican Street
Seattle WA 98109-8059
Phone: 206-221-7316
Fax: 206-616-4274

Research Areas

  • Cancer Immunology
    Innate Immunity

LAB

Postdoc Position Available

Pubmed

Andrew Oberst, PhD

Programmed cell death—cellular suicide—is a fundamental process required for embryonic development, tissue homeostasis, tumor suppression and immunity. We now understand that cells can die in several different ways: in addition to the well-studied process of apoptosis, cells can activate other suicide programs, such as pyroptosis and necroptosis. Importantly, apoptotic cells are rapidly cleared from the body by phagocytes, and apoptosis is generally considered a non-inflammatory event. In contrast, cells dying by pyroptosis or necroptosis release both their contents and specific cytokine signals into surrounding tissues, activating immune cells and promoting both inflammation and adaptive immunity. Pathogen infection may trigger any of these cell death programs (depending on the bug), and various viruses and bacteria encode specific inhibitors of cell death effectors. Oncogenic transformation can also lead to inhibition of cell death signaling, and re-engagement of cell death within tumors is a major goal of cancer therapies. These observations lead to one of the central hypotheses on which the Oberst lab focuses: That how a cell dies—not simply whether it dies—is a key determinant of the innate and adaptive immune response that follows. We use engineered forms of cell death proteins and knockout mouse models to understand how different forms of cell death occur, and to compare the immune response triggered by each in vivo in the context of infection, cancer, and autoimmunity. Specific questions currently under investigation include:

What are the determinants of the immune response to necroptotic cells?
Necroptosis is a form of cellular suicide involving both lytic cell death and the production of inflammatory cytokines. We are investigating how these two immunogenic events are linked, in both engineered cellular models and viral infection.

How does pathogen sensing engage cell death?
Activation of innate immune pattern-sensing pathways such as the Toll-like receptors, RIG-I-like receptors, NOD-like receptors or the cGAS-STING pathway can trigger immune cytokine production. These pathways can also lead to apoptosis, pyroptosis, or necroptosis, depending on the cell and tissue context in which they occur. We study the causes and consequences of these cell death programs.

Are there death-independent roles of the cell death machinery? (Yes, there are.)
Mice lacking necroptotic effector proteins are highly susceptible to multiple types of viral infection. Surprisingly however, in some cases this susceptibility is not due to a failure to trigger cell death, but rather to non-death functions of these proteins in innate immune signaling.

How does activation of inflammatory cell death alter models of cancer and autoimmunity? Promoting inflammation and an immune response to dying cells may be beneficial in the context of infection or cancer, but an overexuberant immune response to dying cells can lead to autoimmunity. We have created engineered cell death effectors that allow us to induce specific forms of cell death in vivo. We are applying these systems to models of tumorigenesis, type-I diabetes, and lupus.

Selected publications

  1. Daniels BP, Snyder AG, Olsen TM, Orozco S, Oguin III TH, Tait SWG, Martinez J, Gale, Jr. M, Loo YM, and Oberst A. RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation. Cell 2017 Apr 6;169(2):301-313
  2. Gutierrez KD, Davis MA, Daniels BP, Olsen TM, Ralli-Jain P, Tait SW, Gale M Jr, Oberst A. MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D. 2017 J Immunol.198(5):2156-2164
  3. Nogusa S, Thapa RJ, Dillon CP, Liedmann S, Oguin TH, Ingram JP, Kosoff R, Sharma S, Sturm O, Verbist K, Gough PJ, Bertin J, Hartmann B, Sealfon SC, Kaiser WJ, Mocarski ES, López CB, Thomas PG, Oberst A*, Green DR*, and Balachandran S*. RIPK3 activates parallel pathways of FADD-mediated apoptosis and MLKL-driven necroptosis to protect against influenza A virus. Cell Host & Microbe, 2016 Cell Host Microbe. 20(1) *Co-corresponding authors
  4. Kolb JP, Oguin TH 3rd, Oberst A, Martinez J. Programmed Cell Death and Inflammation: Winter Is Coming. Trends Immunol, in press (Review)
  5. Yatim N, Jusforgues-Saklani H, Orozco S, Schulz O, Barreira da Silva R, Reis e Sousa C, Green DR, Oberst A, Albert ML. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8⁺ T cells. Science . 2015 Oct 16;350(6258):328-34. doi: 10.1126/science.aad0395. Epub 2015 Sep 24. PubMed PMID: 26405229.
  6. Oberst A. Death in the fast lane: what's next for necroptosis? FEBS J. 2015 Sep 23. doi: 10.1111/febs.13520. [Epub ahead of print] Review. PubMed PMID: 26395133.
  7. Orozco S, Yatim N, Werner MR, Tran H, Gunja SY, Tait SW, Albert ML, Green DR, Oberst A . RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ . 2014 Oct;21(10):1511-21. doi: 10.1038/cdd.2014.76. Epub 2014 Jun 6. PubMed PMID: 24902904; PubMed Central PMCID: PMC4158689.
  8. Tait SW*, Oberst A*, Quarato G, Milasta S, Haller M, Wang R, Karvela M, Ichim G, Yatim N, Albert ML, Kidd G, Wakefield R, Frase S, Krautwald S, Linkermann A, Green DR. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep . 2013 Nov 27;5(4):878-85. doi: 10.1016/j.celrep.2013.10.034. Epub 2013 Nov 21. PubMed PMID: 24268776; PubMed Central PMCID: PMC4005921.
  9. Oberst A. Autophagic cell death RIPs into tumors. Cell Death Differ. 2013 Sep;20(9):1131-2. doi: 10.1038/cdd.2013.89. PubMed PMID: 23933887; PubMed Central PMCID: PMC3741513.
  10. Oberst A, Green DR. It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival.Nat Rev Mol Cell Biol . 2011 Oct 21;12(11):757-63. doi: 10.1038/nrm3214. PubMed PMID: 22016059; PubMed Central PMCID: PMC3627210.
  11. Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature . 2011 Mar 17;471(7338):363-7. doi: 10.1038/nature09852. Epub 2011 Mar 2. PubMed PMID: 21368763; PubMed Central PMCID: PMC3077893.
  12. Pop C*, Oberst A*, Drag M, Van Raam BJ, Riedl SJ, Green DR, Salvesen GS. FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J . 2011 Feb 1;433(3):447-57. doi: 10.1042/BJ20101738. PubMed PMID: 21235526; PubMed Central PMCID: PMC4024219.
  13. Oberst A*, Pop C*, Tremblay AG, Blais V, Denault JB, Salvesen GS, Green DR. Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation. J Biol Chem . 2010 May 28;285(22):16632-42. doi: 10.1074/jbc.M109.095083. Epub 2010 Mar 22.
B.S., Biology,  Amherst Colege
Ph.D., Biochemistry and Molecular Biology, Universitá di Tor Vergara (Rome) & Université Pierre et Marie Curie (Paris)
 

Graduate Students
Michelle Brault, mrb318@uw.edu
Nick Hubbard, nwhubbard@gmail.com
Susana Orozco, slorozco@uw.edu
Annelise Snyder, agsnyder@uw.edu

Postdoctoral Fellows
Brian Daniels, bdaniels@uw.edu
Michelle Messmer, mmessmer@uw.edu

Laboratory Staff
Pooja Jain, jainp1@uw.edu