Identification of cellular restriction factors against herpesviral infection
Final Report Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesviruses causing severe disease in immunocompromised individuals. Members of the TRIM protein family, like TRIM5a for retroviruses or TRIM19/PML for various viruses have been shown to act as antiviral factors by playing key roles in antiviral immune signaling or by directly interfering with the viral replication cycle. Using a screening approach, I could show that knockdown of 15 out of 62 human TRIM proteins leads to a significant increase in lytic reactivation of latent KSHV. Further studies focused on the role of TRIM43 in the restriction of KSHV because i) TRIM43 also restricts the replication of Herpes-simplex 1 virus and Dengue virus ii) TRIM43 is highly upregulated upon herpesviral infection and iii) TRIM43 is a protein with unknown function. I could demonstrate by electron microscopy and confocal microscopy, that TRIM43 is a centrosomal protein. Upon herpesviral infection, TRIM43 gets highly upregulated and can be detected in dot like accumulations in the cytoplasm. The upregulation of TRIM43 upon herpesviral infection is mediated by the germline transcription factor DUX4. In addition, by identifying interaction partners of TRIM43 by mass spectrometry it could be demonstrated, that TRIM43 is an ubiquitin-E3 ligase for Pericentrin and mediates the proteasomal degradation of Pericentrin. Pericentrin is a key component of the pericentrosomal material (PCM) and has been shown to be essential for natural centrosome function. Along this line, overexpression of TRIM43 as seen during herpesviral infection leads to a degradation of Pericentrin and subsequently to a loss of centrosomes in the cell. Taken together this study establishes TRIM43 as a novel intrinsic restriction factor for herpesviruses an in addition as an important cellular protein regulating centrosome function.
Publications
- (2014) Antagonism of the Phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5. Cell Host & Microbe. 9;16(1):19-30
Davis ME, Wang MK, Rennick LJ, Full F, Mesman AW, Gringhuis SI, Geijtenbeek TBH, Duprex WP, and Gack MU
(See online at https://doi.org/10.1016/j.chom.2014.06.007) - (2014) Prostaglandin E2: the villain in the host response to influenza virus. Immunity. 17;40(4):453-4
Full F, Gack MU
(See online at https://doi.org/10.1016/j.immuni.2014.03.008) - (2015) Delicate coordination of TRIM21's dual activity in virus neutralization and signaling. Proc Natl Acad Sci USA. 11;112(32):9797-8
Full F, Gack MU
(See online at https://doi.org/10.1073/pnas.1512642112) - (2016) Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner. Front. Microbiol. 09 June 2016
Proff J, Walterskirchen C, Brey C, Geyeregger R, Full F, Ensser A, Lehner M and Holter W
(See online at https://doi.org/10.3389/fmicb.2016.00844)
