Innate immunity and innate immune evasion

Principal investigator

Dr. Marjolein Kikkert

MERS-CoV PLpro+UbDescription of the research

The first line of defense against viral infection is formed by the innate immune response. In addition to phosphorylation, signaling pathways involved in innate immunity are extensively regulated by ubiquitination. Depending on the way ubiquitin is bound, ubiquitination induces targeting of the substrate protein to the proteasome for degradation, or activation of the target stimulating downstream signaling. Ubiquitin-mediated regulation of signaling pathways involved in innate immunity provides an opportunity for negative feedback as well as viral immune evasion since ubiquitination is a reversible process, with the de-conjugation of ubiquitin being performed by deubiquitinating enzymes (DUBs). Previously, members of two unrelated groups of RNA viruses, the arteri- and nairoviruses, were found to encode a protease that resembles the ovarian tumor domain-containing (OTU) subclass of DUBs. Also the coronaviruses encode a DUB, however these proteases resemble the ubiquitin specific protease (USP) class of DUBs. We study the role of viral OTU-DUBs in the negative regulation of innate immune signaling during virus infection. We use this knowledge to design potential recombinant vaccine viruses from which this actvity is specifically removed without affecting the basic capacity of the virus to replicate, thus increasing innate immune response against the vaccine virus. Since the proteases containing deubiquitinating activity are part of the membrane-bound  replicationenzyme complex, we are also studying the possible relation between the DUB activity and the morphogenesis and function of the virus-induced membrane modifications.

Research Topics

  • Innate immunity
  • Innate immune evasion by +RNA viruses
  • Viral deubiquitinases
  • Molecular pathogenesis of +RNA virus infection

Key Publications

  • Structure and Function of Viral Deubiquitinating Enzymes. Bailey-Elkin BA, Knaap RCM, Kikkert M, Mark BL. J Mol Biol. 2017 Nov 10;429(22):3441-3470
  • Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants. Zhang W, Bailey-Elkin BA, Knaap RCM, Khare B, Dalebout TJ, Johnson GG, van Kasteren PB, McLeish NJ, Gu J, He W, Kikkert M, Mark BL, Sidhu SS. PLoS Pathog. 2017 May 18;13(5):e1006372.
  • Crystal structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression. Bailey-Elkin BA, Knaap RC, Johnson GG, Dalebout TJ, Ninaber DK, van Kasteren PB, Bredenbeek PJ, Snijder EJ, Kikkert M, Mark BL. J Biol Chem. 2014; 289:34667-82.
  • Viral OTU deubiquitinases: A structural and functional comparison. Bailey-Elkin BA, van Kasteren PB, Snijder EJ, Kikkert M, Mark BL. Plos Pathog. 2014; 10:e1003894.
  • Deubiquitinase function of arterivirus papain-like protease 2 suppresses the innate immune response in infected host cells. van Kasteren PB, Bailey-Elkin BA, James TW, Ninaber DK, Beugeling C, Khajehpour M, Snijder EJ, Mark BL, Kikkert M. Proc Natl Acad Sci USA. 2013; 110:E838-47.
  • Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers. Oudshoorn D, Versteeg GA, Kikkert M. Cytokine Growth Factor Rev. 2012; 23:273-82.
  • Arterivirus and nairovirus ovarian tumor domain-containing deubiquitinases target activated RIG-I to control innate immune signaling. van Kasteren PB, Beugeling C, Ninaber DK, Frias-Staheli N, van Boheemen S, García-Sastre A, Snijder EJ, and Kikkert M. J Virol. 2012; 86:773-785.
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