Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

Chao Qin; Rui Zhang; Yue Lang; Anwen Shao; Aotian Xu; Wenhai Feng; Jun Han; Mengdong Wang; Wanwei He; Cuilian Yu; Jun Tang

doi:10.1371/journal.ppat.1007559

Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

PLoS Pathog. 2019 Jan 25;15(1):e1007559. doi: 10.1371/journal.ppat.1007559. eCollection 2019 Jan.

Authors

Chao Qin¹, Rui Zhang¹, Yue Lang¹, Anwen Shao², Aotian Xu¹, Wenhai Feng², Jun Han¹, Mengdong Wang¹, Wanwei He¹, Cuilian Yu¹, Jun Tang¹

Affiliations

¹ State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
² Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China.

Abstract

Type I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon-α (IFNα) -mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFNα, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFNα-induced antiviral immunity and in the control of viral infections.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alphaherpesvirinae / metabolism
Alphaherpesvirinae / pathogenicity
Animals
Cell Line
China
Herpesvirus 1, Human / metabolism
Herpesvirus 1, Suid / metabolism
Humans
Immunity, Innate / drug effects
Interferon Type I / immunology
Interferon-Stimulated Gene Factor 3, alpha Subunit / metabolism
Interferon-alpha / metabolism
Interferons / immunology
Interferons / metabolism*
Mice
Mice, Inbred BALB C
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Repressor Proteins / metabolism*
Repressor Proteins / physiology
Response Elements
STAT1 Transcription Factor / metabolism
STAT2 Transcription Factor / metabolism
Signal Transduction / immunology
Tumor Suppressor Proteins / metabolism*
Tumor Suppressor Proteins / physiology
Viral Proteins / genetics
Viral Proteins / metabolism*
Virus Diseases / genetics

Substances

BCLAF1 protein, human
Interferon Type I
Interferon-Stimulated Gene Factor 3, alpha Subunit
Interferon-alpha
Repressor Proteins
STAT1 Transcription Factor
STAT2 Transcription Factor
Tumor Suppressor Proteins
Viral Proteins
Interferons
Protein Serine-Threonine Kinases
US3 protein, Human herpesvirus 1

Grants and funding

This work was supported by the National Key Research and Development Program of China (grant 2016YFD0500100), the National Natural Science Foundation of China (grant 31500703), and the State Key Laboratory of Agrobiotechnology (grant 2018SKLAB1-6). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.