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 and Harry B. Greenberg ()
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Siyuan Ding: Stanford University
Jonathan Diep: Stanford University
Ningguo Feng: Stanford University
Lili Ren: Stanford University
Bin Li: Jiangsu Academy of Agricultural Sciences
Yaw Shin Ooi: Stanford University
Xin Wang: Cleveland Clinic
Kevin F. Brulois: VA Palo Alto Health Care System
Linda L. Yasukawa: Stanford University
Xingnan Li: Stanford University
Calvin J. Kuo: Stanford University
David A. Solomon: University of California
Jan E. Carette: Stanford University
Harry B. Greenberg: Stanford University

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03782-z

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