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Innate immunity is a fundamental defence response that depends on evolutionarily conserved pattern recognition receptors for sensing infections or danger signals (1,2). Nucleotide-binding and oligomerization domain (NOD) proteins are cytosolic pattern-recognition receptors of paramount importance in the intestine, and their dysregulation is associated with inflammatory bowel disease (3,4). They sense peptidoglycans from commensal microorganisms and pathogens and coordinate signalling events that culminate in the induction of inflammation and anti-microbial responses (2). However, the signalling mechanisms involved in this process are not fully understood. Here, using genome-wide RNA interference, we identify candidate genes that modulate the NOD1 inflammatory response in intestinal epithelial cells. Our results reveal a significant crosstalk between innate immunity and apoptosis and identify BID, a BCL2 family protein, as a critical component of the inflammatory response. Colonocytes depleted of BID or macrophages from [Bid.sup.-/-] mice are markedly defective in cytokine production in response to NOD activation. Furthermore, [Bid.sup.-/-] mice are unresponsive to local or systemic exposure to NOD agonists or their protective effect in experimental colitis. Mechanistically, BID interacts with NOD1, NOD2 and the IκB kinase (IKK) complex, impacting NF-κB and extracellular signal-regulated kinase (ERK) signalling. Our results define a novel role of BID in inflammation and immunity independent of its apoptotic function, furthering the mounting evidence of evolutionary conservation between the mechanisms of apoptosis and immunity., To identify novel regulators of the NOD1 pathway, we conducted a small interfering RNA (siRNA) screen using a library targeting 7,170 human druggable genes. The human intestinal epithelial cell-line HT29 [...]

Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development (1), T-lymphocyte activation (2), and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands (3,4). Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long ([FLIP.sub.L], also known as CFLAR), and this complex is required for the protective function., The death receptor pathway of apoptosis is induced by ligation of a subset of tumour necrosis factor (TNF) receptor super-family members (the death receptors) (5). This pathway involves the recruitment [...]

Author(s): Miguel A. Sanjuan [1]; Christopher P. Dillon [1]; Stephen W. G. Tait [1]; Simon Moshiach [2]; Frank Dorsey [3]; Samuel Connell [1]; Masaaki Komatsu [4]; Keiji Tanaka [4]; John [...]

Nature 488, E6-E8(2012); doi: 10.1038/nature11367 In our Reply to the Brief Communications Arising 'Is BID required for NOD signalling?' we made use of a figure generated by the authors of [...]

Caspase-8 has two opposing biological functions-it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL, also known as CFLAR), and this complex is required for the protective function. [ABSTRACT FROM AUTHOR]