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The deubiquitinase activity of A20 is dispensable for NF‐κB signaling

Arnab De, Teruki Dainichi, Chozha Vendan Rathinam, Sankar Ghosh

Author Affiliations

  1. Arnab De1,
  2. Teruki Dainichi1,
  3. Chozha Vendan Rathinam2 and
  4. Sankar Ghosh*,1
  1. 1Department of Microbiology and Immunology, College of Physicians & Surgeons Columbia University, New York, NY, USA
  2. 2Department of Genetics and Development, College of Physicians & Surgeons Columbia University, New York, NY, USA
  1. *Corresponding author. Tel: +1 212 304 5257; E‐mail: sg2715{at}columbia.edu
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Abstract

A20 has been suggested to limit NF‐κB activation by removing regulatory ubiquitin chains from ubiquitinated substrates. A20 is a ubiquitin‐editing enzyme that removes K63‐linked ubiquitin chains from adaptor proteins, such as RIP1, and then conjugates them to K48‐linked polyubiquitin chains to trigger proteasomal degradation. To determine the role of the deubiquitinase function of A20 in downregulating NF‐κB signaling, we have generated a knock‐in mouse that lacks the deubiquitinase function of A20 (A20‐OTU mice). These mice are normal and have no signs of inflammation, have normal proportions of B, T, dendritic, and myeloid cells, respond normally to LPS and TNF, and undergo normal NF‐κB activation. Our results thus indicate that the deubiquitinase activity of A20 is dispensable for normal NF‐κB signaling.

See also: K Verhelst et al

Synopsis

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The deubiquitinase activity of the ubiquitin‐editing enzyme A20 has been suggested to regulate NF‐κB activation. This study shows, through the use of knock‐in mice, that A20 deubiquitinase activity is in fact dispensable for NF‐κB signaling.

  • Knock‐in mice containing C103A A20 (A20‐OTU), which lacks deubiquitinase activity, do not have an inflammatory phenotype.

  • Immune cells from A20‐OTU mice show normal LPS‐ and TNF‐ induced NF‐κB activation and downstream gene expression, comparable to cells from wild‐type mice.

  • Loss of A20 deubiquitinase function does not exacerbate inflammatory responses in vivo in a septic shock model.

  • Received December 3, 2013.
  • Revision received April 20, 2014.
  • Accepted April 24, 2014.
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