Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

Abstract

T follicular helper (Tfh) cells are essential providers of help to B cells. The transcription factor B-cell CLL/lymphoma 6 (Bcl6) is a lineage-defining regulator of Tfh cells and germinal center B cells. In B cells, Bcl6 has the potential to recruit distinct transcriptional corepressors through its BTB domain or its poorly characterized middle domain (also known as RDII), but in Tfh cells the roles of the Bcl6 middle domain have yet to be clarified. Mimicked acetylation of the Bcl6 middle domain (K379Q) in CD4 T cells results in significant reductions in Tfh differentiation in vivo. Blimp1 (Prdm1) is a potent inhibitor of Tfh cell differentiation. Although Bcl6 K379Q still bound to the Prdm1 cis-regulatory elements in Tfh cells, Prdm1 expression was derepressed. This was a result of the failure of Bcl6 K379Q to recruit metastasis-associated protein 3 (MTA3). The loss of Bcl6 function in Bcl6 K379Q-expressing CD4 T cells could be partially rescued by abrogating Prdm1 expression. In addition to Prdm1, we found that Bcl6 recruits MTA3 to multiple genes involved in Tfh cell biology, including genes important for cell migration, cell survival, and alternative differentiation pathways. Thus, Bcl6 middle domain mediated repression is a major mechanism of action by which Bcl6 controls CD4 T-cell fate and function.

Regulation of hematopoietic development by ZBTB transcription factors

“…The KKYK motif also mediates direct interaction with metastasis-associated protein 3 (MTA3) [70], a subunit of the NuRD complex. Strikingly, mice harboring either the Bcl6 QQYQ or Bcl6 KKYQ mutation largely phenocopy Bcl6 KO mice [71, 72], suggesting that BCL6 acetylation serves as a molecular switch governing BCL6-mediated repression in vivo. The BCL6 RD2 also contains a PEST motif, which is phosphorylated by mitogen-activated protein kinase (MAPK) following B cell receptor (BCR) signaling [73].…”

“…Since T cell-specific Bcl6 inactivation also abrogates GC formation [108–110], Bcl6 likely regulates GC formation through at least three distinct mechanisms: (1) induction of Tfh cell development; (2) initiation of pre-GCB cell migration to the follicle; and (3) support of GCB cell proliferation and survival. Notably, two groups independently showed that co-repressor recruitment via BCL6-BTB domain is necessary for GC development in vivo, although there remain discrepancies regarding the contribution of Tfhs to observed phenotypes [57, 71, 72, 113]. …”

BCL6 represses antiviral resistance in follicular T helper cells

“…Each of these domains can associate with specific corepressor complexes in B cells and macrophages. Both the RD2 domain and BCL6 BTB domain have been shown to be important in Tfh cell function in vivo [44][45][46]. We found that RI-BPI, a peptide inhibitor that can disrupt the association of the BCL6 BTB domain with its corepressors, was able to up-regulate Tfh ISG expression, suggesting the BCL6 BTB domain is critically important in suppressing ISG expression in Tfh cells.…”

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+ T-Cell Activation

“…HIC1 acetylation on K314 in the MKHEP SUMOylation/acetylation motif negatively regulates its interaction with MTA1, whereas its SUMOylation favors it, notably in the DNA damage response (40,59). BCL6 acetylation on K379 in the KKYK motif abrogates its ability to interact with MTA3, which is a major repression mechanism controlling germinal center B-cell differentiation (60)(61)(62) as well as CD4 ϩ T-cell fate and function (63). Although our studies have been focused on BCL11B, it is tempting to speculate that similar PTMs could be identified in other MSRRKQ-containing nuclear proteins.…”