STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection

Siyuan Ding; Jonathan Diep; Ningguo Feng; Lili Ren; Bin Li; Yaw Shin Ooi; Xin Wang; Kevin F Brulois; Linda L Yasukawa; Xingnan Li; Calvin J Kuo; David A Solomon; Jan E Carette; Harry B Greenberg

doi:10.1038/s41467-018-03782-z

STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection

Nat Commun. 2018 Apr 16;9(1):1485. doi: 10.1038/s41467-018-03782-z.

Authors

Siyuan Ding^{1

2

3}, Jonathan Diep¹, Ningguo Feng^{1

2

3}, Lili Ren^{1

2

3

4}, Bin Li⁵, Yaw Shin Ooi¹, Xin Wang^{6

7}, Kevin F Brulois^{3

8}, Linda L Yasukawa^{1

2

3}, Xingnan Li⁹, Calvin J Kuo⁹, David A Solomon¹⁰, Jan E Carette¹, Harry B Greenberg^{11

12

13}

Affiliations

¹ Department of Microbiology and Immunology, Stanford University, Stanford, CA, 94305, USA.
² Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, 94305, USA.
³ Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
⁴ School of Pharmaceutical Sciences, Nanjing Tech University, 211816, Nanjing, China.
⁵ Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, 210014, Nanjing, China.
⁶ Department of Immunology, Cleveland Clinic, Cleveland, OH, 44195, USA.
⁷ Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, 266071, Qingdao, China.
⁸ Department of Pathology, Stanford University, Stanford, CA, 94305, USA.
⁹ Department of Medicine, Division of Hematology, Stanford University, Stanford, CA, 94305, USA.
¹⁰ Department of Pathology, University of California, San Francisco, CA, 94143, USA.
¹¹ Department of Microbiology and Immunology, Stanford University, Stanford, CA, 94305, USA. [email protected].
¹² Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, 94305, USA. [email protected].
¹³ Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA. [email protected].

Abstract

Cohesin is a multi-subunit nuclear protein complex that coordinates sister chromatid separation during cell division. Highly frequent somatic mutations in genes encoding core cohesin subunits have been reported in multiple cancer types. Here, using a genome-wide CRISPR-Cas9 screening approach to identify host dependency factors and novel innate immune regulators of rotavirus (RV) infection, we demonstrate that the loss of STAG2, an important component of the cohesin complex, confers resistance to RV replication in cell culture and human intestinal enteroids. Mechanistically, STAG2 deficiency results in spontaneous genomic DNA damage and robust interferon (IFN) expression via the cGAS-STING cytosolic DNA-sensing pathway. The resultant activation of JAK-STAT signaling and IFN-stimulated gene (ISG) expression broadly protects against virus infections, including RVs. Our work highlights a previously undocumented role of the cohesin complex in regulating IFN homeostasis and identifies new therapeutic avenues for manipulating the innate immunity.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antigens, Nuclear / genetics
Antigens, Nuclear / immunology*
CRISPR-Cas Systems
Caco-2 Cells
Cell Cycle Proteins / genetics
Cell Cycle Proteins / immunology*
Cell Nucleus / immunology
Cell Nucleus / virology
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / immunology*
Cohesins
DNA Damage
Gene Deletion
Gene Editing
Gene Expression Regulation
Genome, Human
HEK293 Cells
HT29 Cells
HeLa Cells
Host-Pathogen Interactions*
Humans
Interferons / genetics
Interferons / immunology
Intestinal Mucosa / immunology
Intestinal Mucosa / virology
Janus Kinases / genetics
Janus Kinases / immunology
Membrane Proteins / genetics
Membrane Proteins / immunology*
Nucleotidyltransferases / genetics
Nucleotidyltransferases / immunology*
Rotavirus / growth & development
Rotavirus / immunology*
STAT Transcription Factors / genetics
STAT Transcription Factors / immunology
Signal Transduction
Spheroids, Cellular / immunology*
Spheroids, Cellular / virology

Substances

Antigens, Nuclear
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Membrane Proteins
STAG2 protein, human
STAT Transcription Factors
STING1 protein, human
Interferons
Janus Kinases
Nucleotidyltransferases
cGAS protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding