The Roles of RARRES1 and SIRT1/2 in B Cell Function and Homeostasis

Abstract

Upon cognate antigen encounter, naïve (antigen-inexperienced) B cells activate shifting from a state of quiescence to rapid clonal expansion and differentiation into germinal center (GC) B cells, antibody-secreting plasma cells (PCs), and memory B cells. During activation, B cell receptor (BCR) editing, in the form of somatic hypermutation (SHM) and class switch recombination (CSR), is initiated resulting in the production of high affinity and class diverse antibodies. Most lymphomas are of B cell origin, and specifically, of activated GC-derived B cells. In addition, normal aging leads to disruption of B cell activation and function, along with increased risk for B cell malignancy. A full understanding of the mechanistic causes of B cell aging and lymphomagenesis is lacking. Here, we study the roles of the proteins retinoic acid receptor responder 1 (RARRES1) and sirtuins (SIRTs) 1 and 2 in the process of B cell activation, differentiation, and homeostasis.

RARRES1 is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive RARRES1 knockout (RARRES1-/-) mouse models to study RARRES1 function in vivo, and show that RARRES1 loss leads to a dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation RARRES1-/- B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. RARRES1 ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). These findings reveal that RARRES1 is a bona fide tumor suppressor in vivo, promotes cell survival, and reduces B cell differentiation.

SIRTs are a family of conserved NAD+-dependent deacetylases that regulate gene expression, cell cycle progression, differentiation, and cell survival. Here, we show SIRT1 and SIRT2 help regulate GC maturation, CSR, and PC differentiation of B cells. In addition, we observe that SIRT2 is necessary for B cell adaptation to oxidative, genotoxic, and metabolic stress. As SIRTs are implicated in aging such knowledge of SIRTs in B cells may uncover potential therapeutic avenues for rejuvenation and lymphomagenesis prevention of aged B cells.