The mechanism of NEMO recruitment into supramolecular complexes and its dependence on ubiquitination differs in response to the proinflammatory cytokines TNF and IL-1.

Boisson et al. report a human homozygous mutation of HOIP, the gene encoding the catalytic component of the linear ubiquitination chain assembly complex, LUBAC. The missense alleles impair the expression of HOIP, destabilizing the LUBAC complex and resulting in immune cell dysfunction leading to multiorgan inflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectactasia.