Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice

Abstract

Immune homeostasis is a prerequisite to protective immunity against gastrointestinal infections. In Drosophila, immune deficiency (IMD) signalling (tumour necrosis factor receptor/interleukin-1 receptor, TNFR/IL-1R in mammals) is indispensable for intestinal immunity against invading bacteria. However, how this local antimicrobial immune response contributes to inflammatory regulation remains poorly defined. Here, we show that flies lacking intestinal Bap180 (a subunit of the chromatin-remodelling switch/sucrose non-fermentable (SWI/SNF) complex) are susceptible to infection as a result of hyper-inflammation rather than bacterial overload. Detailed analysis shows that Bap180 is induced by the IMD-Relish response to both enteropathogenic and commensal bacteria. Upregulated Bap180 can feed back to restrain overreactive IMD signalling, as well as to repress the expression of the pro-inflammatory gene eiger (TNF), a critical step to prevent excessive tissue damage and elongate the lifespan of flies, under pathological and physiological conditions, respectively. Furthermore, intestinal targeting of Baf180 renders mice susceptible to a more aggressive infectious colitis caused by Citrobacter rodentium. Together, Bap180 and Baf180 serve as a conserved transcriptional repressor that is critical for the maintenance of innate immune homeostasis in the intestines.

PBRM1 regulates the stress response in epithelial cells

“…In support of this, a recent CRISPR-Cas9 screen identified PBRM1, along with other PBAF-specific subunits, as resistance factors against T-cell mediated killing (Pan et al, 2018). This is related to a general role for PBRM1 in suppressing the inflammatory response, as PBRM1 deletion also increases innate immunity hyperinflammation in the gut (He et al, 2017;Shu et al, 2017). The general role for PBRM1 in the stress response could relate to PBRM1's role in suppressing inflammation (and T-cell mediated toxicity) through the regulation of homeostasis (Chovatiya and Medzhitov, 2014), although that connection will need to be explored further.…”

PBRM1 Regulates Stress Response in Epithelial Cells

“…In support of this, a recent CRISPR-Cas9 screen identified PBRM1, along with other PBAF-specific subunits, as resistance factors against T cell-mediated killing (Pan et al., 2018). This is related to a general role for PBRM1 in suppressing the inflammatory response, as PBRM1 deletion also increases innate immunity hyperinflammation in the gut (He et al., 2017, Shu et al., 2017). The general role for PBRM1 in stress response could relate to PBRM1's role in suppressing inflammation (and T cell-mediated toxicity) through the regulation of homeostasis (Chovatiya and Medzhitov, 2014), although that connection will need to be explored further.…”

Osa-Containing Brahma Complex Regulates Innate Immunity and the Expression of Metabolic Genes in Drosophila

“…In addition, when looking at protein-protein interactions in the Imd pathway, members of the Brm complex (BAP60, BAP55; Moira) were identified (71). Furthermore, He and coworkers (72) have recently shown that Polybromo/BAP180, the core member of the PBAP complex, is needed to maintain homeostasis in the Drosophila intestine upon immune activation -bap180 mutant flies have a hyperactivated immune response in the midgut in the Erwinia carotovora carotovora 15 (Ecc15) infection model. In these conditions, Bap180 would act as a transcriptional repressor, so the hyperactivation in bap180 mutants is proposed to happen via increased eiger expression without the repressor being present.…”