Optimal Functional Levels of Activation-induced Deaminase Specifically Require the Hsp40 DnaJa1

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2011 Nov 17

PMID 22085931

Citations 23

Authors

Alexandre Orthwein

Astrid Zahn

Stephen P Methot

David Godin

Silvestro G Conticello

Kazutoyo Terada

Javier M Di Noia

Affiliations

Soon will be listed here.

Abstract

The enzyme activation-induced deaminase (AID) deaminates deoxycytidine at the immunoglobulin genes, thereby initiating antibody affinity maturation and isotype class switching during immune responses. In contrast, off-target DNA damage caused by AID is oncogenic. Central to balancing immunity and cancer is AID regulation, including the mechanisms determining AID protein levels. We describe a specific functional interaction between AID and the Hsp40 DnaJa1, which provides insight into the function of both proteins. Although both major cytoplasmic type I Hsp40s, DnaJa1 and DnaJa2, are induced upon B-cell activation and interact with AID in vitro, only DnaJa1 overexpression increases AID levels and biological activity in cell lines. Conversely, DnaJa1, but not DnaJa2, depletion reduces AID levels, stability and isotype switching. In vivo, DnaJa1-deficient mice display compromised response to immunization, AID protein and isotype switching levels being reduced by half. Moreover, DnaJa1 farnesylation is required to maintain, and farnesyltransferase inhibition reduces, AID protein levels in B cells. Thus, DnaJa1 is a limiting factor that plays a non-redundant role in the functional stabilization of AID.

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