The linear ubiquitin chain–assembly complex (LUBAC) mediates the linear ubiquitination of signaling mediators downstream of various Toll-like receptors to induce activation of the transcription factor NF-κB in fibroblasts and keratinocyes. In The Journal of Experimental Medicine, Rodgers et al. show that in mouse macrophages, the HOIL-1L subunit of LUBAC is required for linear ubiquitination of the adaptor ASC and for assembly of the NLRP3 inflammasome, but not for the activation of NF-κB. HOIL-1L-deficient bone marrow–derived macrophages have normal activation of NF-κB but defective cleavage of pro-caspase-1 and defective formation of NLRP3-ASC complexes after stimulation of NLRP3. The HOIL-1L and HOIP units of LUBAC are both required for the linear, nondegradative ubiquitination of ASC after stimulation. HOIL-1L-deficient mice have diminished NLRP3-dependent production of IL-1β and recruitment of neutrophils in an experimental model of peritonitis and, similar to NLRP3- or ASC-deficient mice, are resistant to lipopolysaccharide-induced sepsis, which indicates a role for LUBAC in inflammasome-dependent inflammation.

J. Exp. Med. (23 June 2014) doi:10.1084/jem.20132486