Adenovirus E1A binding to DCAF10 targets proteasomal degradation of RUVBL1/2 AAA+ ATPases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress

Nathan R Zemke; Emily Hsu; William D Barshop; Jihui Sha; James A Wohlschlegel; Arnold J Berk

doi:10.1128/jvi.00993-23

Adenovirus E1A binding to DCAF10 targets proteasomal degradation of RUVBL1/2 AAA+ ATPases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress

J Virol. 2023 Dec 21;97(12):e0099323. doi: 10.1128/jvi.00993-23. Epub 2023 Nov 14.

Authors

Nathan R Zemke^{1

2

3}, Emily Hsu^{1

3

4}, William D Barshop^{5

6}, Jihui Sha⁵, James A Wohlschlegel^{1

5}, Arnold J Berk^{1

3}

Affiliations

¹ Molecular Biology Institute, University of California, Los Angeles, California, USA.
² Department of Cellular and Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
³ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
⁴ Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁵ Thermo Fisher Scientific, San Jose, California, USA.
⁶ Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, California, USA.

Abstract

Inactivation of EP300/CREBB paralogous cellular lysine acetyltransferases (KATs) during the early phase of infection is a consistent feature of DNA viruses. The cell responds by stabilizing transcription factor IRF3 which activates transcription of scores of interferon-stimulated genes (ISGs), inhibiting viral replication. Human respiratory adenoviruses counter this by assembling a CUL4-based ubiquitin ligase complex that polyubiquitinylates RUVBL1 and 2 inducing their proteasomal degradation. This inhibits accumulation of active IRF3 and the expression of anti-viral ISGs, allowing replication of the respiratory HAdVs in the face of inhibition of EP300/CBEBBP KAT activity by the N-terminal region of E1A.

Keywords: CBP; CRL4; DCAF10; E1A; IRF3; P300; adenovirus; innate immunity; virology.

MeSH terms

ATPases Associated with Diverse Cellular Activities* / metabolism
Adenovirus E1A Proteins* / metabolism
Adenoviruses, Human / enzymology
Adenoviruses, Human / metabolism
Carrier Proteins* / metabolism
Cullin Proteins / metabolism
DNA Helicases* / metabolism
Humans
Immunity, Innate*
Interferons / metabolism
Proteasome Endopeptidase Complex* / metabolism
Protein Structure, Quaternary
Stress, Physiological*
Ubiquitin-Protein Ligase Complexes / chemistry
Ubiquitin-Protein Ligase Complexes / metabolism
Ubiquitination
Virus Replication

Substances

Adenovirus E1A Proteins
ATPases Associated with Diverse Cellular Activities
Carrier Proteins
CUL4B protein, human
Cullin Proteins
DNA Helicases
EP300 protein, human
Interferons
Proteasome Endopeptidase Complex
RUVBL1 protein, human
RUVBL2 protein, human
Ubiquitin-Protein Ligase Complexes
IRF3 protein, human