2. Academic Validation
  3. USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling

USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling

  • Immunohorizons. 2020 Oct 22;4(10):670-678. doi: 10.4049/immunohorizons.2000036.
Wenting Xu 1 2 3,  Jason S Rush 4,  Daniel B Graham 1 2 4,  Zhifang Cao 5 2 4,  Ramnik J Xavier 5 2 4
Affiliations

Affiliations

  • 1 Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
  • 2 Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
  • 3 Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; and.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  • 5 Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; [email protected] [email protected].
PMID: 33093067 DOI: 10.4049/immunohorizons.2000036
Abstract

Posttranslational modifications are efficient means to rapidly regulate protein function in response to a stimulus. Although ubiquitination events and the E3 ubiquitin ligases involved are increasingly characterized in many signaling pathways, their regulation by deubiquitinating enzymes remains less understood. The C-type lectin receptor (CLR) signaling adaptor CARD9 was previously reported to be activated via TRIM62-mediated ubiquitination. In this study, we identify the Deubiquitinase USP15 as a novel regulator of CARD9, demonstrating that USP15 constitutively associates with CARD9 and removes TRIM62-deposited ubiquitin marks. Furthermore, USP15 knockdown and knockout specifically enhance CARD9-dependent CLR signaling in both mouse and human immune cells. Altogether, our study identifies a novel regulator of innate immune signaling and provides a blueprint for the identification of additional deubiquitinases that are likely to control these processes.

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