Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components

Virology. 2002 Dec 20;304(2):160-6. doi: 10.1006/viro.2002.1773.

Abstract

Signal transducer and activator of transcription (STAT) proteins are normally long-lived, but infection with certain Paramyxoviruses results in efficient loss of IFN-responsive STAT1 or STAT2. Expression of a virus-encoded protein called "V" is sufficient to mediate the destruction of STAT proteins. STAT degradation is blocked by proteasome inhibitors, strongly implicating the ubiquitin (Ub)-proteasome targeting system. We demonstrate that cellular expression of V proteins from simian virus 5 (SV5) and type II human parainfluenza virus (HPIV2) induces polyubiquitylation of STAT1 and STAT2 targets. In vitro, the V proteins catalyze Ub transfer in an ATP-dependent process that requires both Ub-activating (E1) and Ub-conjugating (E2) activities. Furthermore, SV5 and HPIV2 V-interacting protein partners were isolated by affinity purification from human cells and reveal a complex of associated cellular proteins. This complex includes both STAT1 and STAT2, and the damaged DNA binding protein, DDB1. In addition, a protein related to a family of cellular Ub ligase complex subunits, cullin 4A (Cul4A), associated with the V proteins. The roles of both DDB1 and Cul4A in STAT1 degradation by SV5 infection were analyzed using small interfering RNAs. These findings demonstrate the assembly of a V-dependent degradation complex that includes STAT1, STAT2, DDB1, and Cul4A. In agreement with prior nomenclature on SCF-type cellular E3 enzymes, we refer to this complex as VDC.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigen-Antibody Complex / metabolism
  • Cells, Cultured
  • Cullin Proteins*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Ligases / metabolism*
  • Neoplasm Proteins / metabolism
  • RNA, Small Interfering / physiology
  • Respirovirus / physiology*
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Trans-Activators / metabolism*
  • Ubiquitin-Protein Ligases
  • Viral Proteins / physiology*
  • Viral Structural Proteins / physiology*

Substances

  • Antigen-Antibody Complex
  • CUL4A protein, human
  • Cullin Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Trans-Activators
  • V protein, Simian parainfluenza virus 5
  • V protein, human parainfluenza virus type 1
  • Viral Proteins
  • Viral Structural Proteins
  • Ubiquitin-Protein Ligases
  • Ligases