SPOC1-Mediated Antiviral Host Cell Response Is Antagonized Early in Human Adenovirus Type 5 Infection

Autor: Andreas Mund, Sabrina Schreiner, Peter Wimmer, Carolin Bürck, Thomas Dobner, Hans Will, Tobias Schubert, Peter Groitl, Sarah Kinkley
Rok vydání: 2013
Předmět:
Zdroj: PLoS Pathogens, Vol 9, Iss 11, p e1003775 (2013)
PLoS Pathogens
ISSN: 1553-7374
DOI: 10.1371/journal.ppat.1003775
Popis: Little is known about immediate phases after viral infection and how an incoming viral genome complex counteracts host cell defenses, before the start of viral gene expression. Adenovirus (Ad) serves as an ideal model, since entry and onset of gene expression are rapid and highly efficient, and mechanisms used 24–48 hours post infection to counteract host antiviral and DNA repair factors (e.g. p53, Mre11, Daxx) are well studied. Here, we identify an even earlier host cell target for Ad, the chromatin-associated factor and epigenetic reader, SPOC1, recently found recruited to double strand breaks, and playing a role in DNA damage response. SPOC1 co-localized with viral replication centers in the host cell nucleus, interacted with Ad DNA, and repressed viral gene expression at the transcriptional level. We discovered that this SPOC1-mediated restriction imposed upon Ad growth is relieved by its functional association with the Ad major core protein pVII that enters with the viral genome, followed by E1B-55K/E4orf6-dependent proteasomal degradation of SPOC1. Mimicking removal of SPOC1 in the cell, knock down of this cellular restriction factor using RNAi techniques resulted in significantly increased Ad replication, including enhanced viral gene expression. However, depletion of SPOC1 also reduced the efficiency of E1B-55K transcriptional repression of cellular promoters, with possible implications for viral transformation. Intriguingly, not exclusive to Ad infection, other human pathogenic viruses (HSV-1, HSV-2, HIV-1, and HCV) also depleted SPOC1 in infected cells. Our findings provide a general model for how pathogenic human viruses antagonize intrinsic SPOC1-mediated antiviral responses in their host cells. A better understanding of viral entry and early restrictive functions in host cells should provide new perspectives for developing antiviral agents and therapies. Conversely, for Ad vectors used in gene therapy, counteracting mechanisms eradicating incoming viral DNA would increase Ad vector efficacy and safety for the patient.
Author Summary Viruses have acquired functions that target and modulate host cell signaling and diverse regulatory cascades, leading to efficient viral propagation. During the course of productive infection, Ad gene products manipulate destruction pathways to prevent viral clearance or cell death prior to viral genome amplification and release of progeny. Recently, we reported that chromatin formation and cellular SWI/SNF chromatin remodeling processes play a key role in Ad transcriptional regulation. Here, we observe for the first time that SPOC1, identified as a regulator of DNA damage response and chromatin structure, plays an essential role in restricting Ad gene expression and progeny production. This host cell antiviral mechanism is efficiently counteracted by tight association with the major core protein pVII bound to the incoming viral genome. Subsequently, SPOC1 undergoes proteasomal degradation via the Ad E1B-55K/E4orf6-dependent, Cullin-based E3 ubiquitin ligase complex. We also show that other viruses from RNA and DNA families also induce efficient degradation of SPOC1. These analyses of evasion strategies acquired by viruses and other human pathogens should provide important insights into factors manipulating the epigenetic environment to potentially inactivate, or amplify host cell immune responses, since detailed molecular mechanisms and the full repertoire of cellular targets still remain elusive.
Databáze: OpenAIRE
Externí odkaz: