PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification.

Verónica Delgado-Benito,Altuna Akalin,Martin Janz,Robert Altwasser,Lisa Keller,Marie-Thérèse Henke,Marieta Caganova,Wiebke Winkler,Ali Rahjouei,Alessandro Prigione,Madlen Driesner,Maria Berruezo-Llacuna,Robin Graf,Sandhya Balasubramanian,Michela Di Virgilio,Devakumar Sundaravinayagam

doi:10.1084/jem.20200137

Abstract

The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.

Highlights

The diversity of our Ig gene repertoire is the result of antibody humoral responses, as evidenced by primary human immunodiversification reactions occurring at different stages of B lym- deficiency syndromes that are caused by defects in these rephocyte development (Dudley et al, 2005; Methot and Di Noia, actions (Durandy et al, 2013).2017)
PDGFA-associated protein 1 (Pdap1) is required for efficient class switch recombination (CSR) To identify novel modulators of mature B cell physiology, we performed loss-of-CSR screens via somatic gene targeting by CRISPR-Cas9 in the B cell lymphoma line CH12
Pdap1 supports physiological levels of activation-induced cytidine deaminase (AID) expression CSR is dependent on cell proliferation (Hasbold et al, 1998, 1999; Hodgkin et al, 1996; Deenick et al, 1999)

Summary

Introduction

V(D)J recombination (Roth, 2014; Dudley et al, 2005) This dues to uracil in single-stranded DNA stretches at the variable process generates unique antibody gene receptors with the po- regions of both Igh and Igl loci during SHM, and within special tential to collectively recognize a formidable number of anti- recombining elements (switch [S] regions) of the Igh during CSR gens. Mature B cells further diversify their Ig genes in the (Bransteitter et al, 2003; Chaudhuri et al, 2003; Petersenperiphery via somatic hypermutation (SHM) and class switch Mahrt et al, 2002; Pham et al, 2003; Sohail et al, 2003; recombination (CSR; Pavri and Nussenzweig, 2011; Methot and Ramiro et al, 2003; Dickerson et al, 2003; Matthews et al, 2014; Di Noia, 2017).

Methods

Results

Conclusion