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Adenovirus exploits the cellular aggresome response to accelerate inactivation of the MRN complex

Yue Liu1, Anna Shevchenko, Andrej Shevchenko

  • 1Molecular Biology Institute and Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095-1570, USA.

Journal of Virology
|October 29, 2005
PubMed

Insights

Adenovirus 5 uses cellular aggresomes to degrade the MRE11-RAD50-NBS1 (MRN) complex, which normally inhibits viral DNA replication. This process accelerates viral replication by inactivating a key cellular defense mechanism.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Aggresomes are cytoplasmic inclusions involved in protein degradation and linked to degenerative diseases.
  • The MRE11-RAD50-NBS1 (MRN) complex is crucial for DNA repair but inhibits adenovirus replication.
  • Adenovirus proteins, such as E1B-55K, can induce aggresome formation.

Purpose of the Study:

  • To investigate the role of cellular aggresomes in adenovirus 5 infection.
  • To determine how adenovirus manipulates the aggresome pathway to facilitate viral replication.
  • To understand the mechanism by which MRN complexes are inactivated during infection.

Main Methods:

  • Adenovirus infection of cells.
  • Expression of viral proteins (E1B-55K, E4orf3, E4orf6).
  • Immunofluorescence microscopy to visualize protein localization and aggresome formation.
  • Co-immunoprecipitation to study protein interactions.
  • Ubiquitination and proteasome degradation assays.

Main Results:

  • Adenovirus 5 utilizes the aggresome pathway to sequester and inactivate MRN complexes.
  • Viral proteins E1B-55K, E4orf3, and E4orf6 are essential for aggresome formation and MRN export to aggresomes.
  • MRN complexes are rapidly degraded by the proteasome within aggresomes after ubiquitination mediated by a viral ligase complex.
  • Aggresome formation accelerates the degradation of cellular proteins, including MRN.

Conclusions:

  • Adenovirus 5 hijacks the cellular aggresome machinery to eliminate MRN complexes, thereby promoting viral DNA replication and packaging.
  • Aggresome formation serves as a critical mechanism for viral evasion of host innate immunity.
  • The findings highlight a novel role for aggresomes in viral pathogenesis and suggest implications for understanding aggresome-related cytotoxicity in degenerative diseases.

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