Modification of proteins with Met1-linked 'linear' ubiquitin chains has emerged 
as a key regulatory signal to control inflammatory signalling via the master 
regulator, the transcription factor nuclear factor κB (NF-κB). While the 
assembly machinery, the linear ubiquitin chain assembly complex (LUBAC), and 
receptors for this ubiquitin chain type have been known for years, it was less 
clear which deubiquitinating enzymes (DUBs) hydrolyse Met1 linkages 
specifically. In 2013, two labs reported the previously unannotated protein 
FAM105B/OTULIN to be this missing Met1 linkage-specific DUB. Structural studies 
have revealed how OTULIN achieves its remarkable specificity, employing a 
mechanism of ubiquitin-assisted catalysis in which a glutamate residue on the 
substrate complements the active site of the enzyme. The specificity of OTULIN 
enables it to regulate global levels of Met1-linked polyubiquitin in cells. This 
ability led to investigations of NF-κB activation from new angles, and also 
revealed involvement of Met1-polyubiquitin in Wnt signalling. Interestingly, 
OTULIN directly interacts with LUBAC, and this interaction is dynamic and can be 
regulated by OTULIN phosphorylation. This provides a new paradigm for how 
individual linkage types can be regulated by dedicated enzyme complexes 
mediating assembly and removal. Here we review what has been learned about 
OTULIN's mechanism, regulation and function, discuss the open questions in the 
field, and discuss how DUBs regulate the NF-κB response.