CRISPR Activation Screening Identifies VGLL3-TEAD1-RUNX1/3 as a Transcriptional Complex for PD-L1 Expression.

Autor:	Wijdeven RH; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands; r.h.m.wijdeven@lumc.nl j.j.c.neefjes@lumc.nl., Cabukusta B; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands., Behr FM; Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands; and., Qiu X; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI., Amiri D; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI., Borras DM; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands., Arens R; Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands; and., Liang Y; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI., Neefjes J; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands; r.h.m.wijdeven@lumc.nl j.j.c.neefjes@lumc.nl.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2022 Sep 01; Vol. 209 (5), pp. 907-915. Date of Electronic Publication: 2022 Aug 03.
DOI:	10.4049/jimmunol.2100917
Abstrakt:	The PD-L1/2-PD-1 immune checkpoint is essential for the proper induction of peripheral tolerance and limits autoimmunity, whereas tumor cells exploit their expression to promote immune evasion. Many different cell types express PD-L1/2, either constitutively or upon stimulation, but the factors driving this expression are often poorly defined. In this study, using genome-wide CRISPR activation screening, we identified three factors that upregulate PD-L1 expression: GATA2, MBD6, and transcription cofactor vestigial-like protein 3 (VGLL3). VGLL3 acts as a transcriptional regulator, and its expression induced PD-L1 in many different cell types. Conversely, loss of VGLL3 impaired IFN-γ-induced PD-L1/2 expression in human keratinocytes. Mechanistically, by performing a second screen to identify proteins acting in concert with VGLL3, we found that VGLL3 forms a complex with TEAD1 and RUNX1/3 to drive expression of PD-L1/2. Collectively, our work identified a new transcriptional complex controlling PD-L1/2 expression and suggests that VGLL3, in addition to its known role in the expression of proinflammatory genes, can balance inflammation by upregulating the anti-inflammatory factors PD-L1 and PD-L2. (Copyright © 2022 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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