Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain.
Transcription regulators STAT1 and STAT2 are key components of the interferon signaling system leading to innate antiviral immunity. The related STAT3 protein is a regulator of interleukin-6-type cytokine signals and can contribute to both cell growth and death important for cancer gene regulation and tumor survival. These three STAT proteins are targeted for proteasome-mediated degradation by RNA viruses in the Rubulavirus genus of the Paramyxoviridae. A single viral protein, the V protein, assembles STAT-specific ubiquitin ligase complexes from cellular components. Simian virus 5 (SV5) targets STAT1, human parainfluenza virus 2 targets STAT2, and mumps virus targets both STAT1 and STAT3. Analysis of the V-dependent degradation complex (VDC) composition and assembly revealed several features contributing to targeting specificity. SV5 and mumps V proteins require STAT2 to recruit the STAT1 target, yet mumps V protein binds STAT3 independent of STAT1 and STAT2. All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting. Protein interaction analysis reveals that paramyxovirus V proteins can homo- and heterooligomerize and that the conserved cysteine-rich zinc-binding C-terminal domain is necessary and sufficient for oligomerization. Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations.
Ulane
Christina M
CM
Mount Sinai School of Medicine, New York, New York 10029, USA.
Kentsis
Alex
A
Cruz
Cristian D
CD
Parisien
Jean-Patrick
JP
Schneider
Kristi L
KL
Horvath
Curt M
CM
D002352:Carrier Proteins / Q000502:physiology; D044842:Cullin Proteins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D019281:Dimerization; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*; D014764:Viral Proteins / Q000737:chemistry* / Q000502:physiology
C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C479529:RBX1 protein, human; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D025801:Ubiquitin; C502891:V protein, Paramyxovirus; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases