In this issue of The EMBO Journal, a multi‐layered global proteome resource, which comprehensively covers TNF‐induced phosphorylation and ubiquitination events as well as receptor interactions, has led to identification of SPATA2 as a novel player that contributes to TNF signalling by interacting with the LUBAC ubiquitin ligase and the CYLD deubiquitylase. Loss of SPATA2 augments transcriptional activation of NF‐κB and limits TNF‐induced necroptosis. A separate screen published in EMBO Reports corroborates these findings by showing that SPATA2 deficiency regulates CYLD activity, TNF‐induced NF‐κB signalling and cell death.
See also: SA Wagner et al and
L Schlicher et al
The Spartans, famed for their brevity of speech, gave rise to the adjective laconic, meaning of few words, but literally, from Laconia, the kingdom of Sparta. For example, when asked by Philip of Macedon, who was threatening the Spartans with invasion, whether they wished that he should come as a “friend” or a “foe”; they replied, “Neither”. While it is impossible to match Spartan wit, Wagner et al (2016) have employed an impressive proteome‐wide quantitative mass spectrometry (MS) approach to dissect the molecular cascade of phosphorylation and ubiquitylation events that follow stimulation with TNF, one of the most studied signalling pathways in biology. Surprisingly, in addition to revealing a series of unknown post‐translational modifications, which we discuss below, this analysis yielded identification of a novel player in the TNF signalling pathway, spermatogenesis associated 2 (SPATA2), which, like its namesake, helps maintain the brevity of TNF signalling. SPATA2 interacts with the LUBAC component HOIP and the deubiquitylase (DUB) CYLD and is required for the recruitment of CYLD to the TNF signalling complex. SPATA2 was also identified as a CYLD interacting protein in a separate screen by Schlicher et al (2016), and both groups show that loss of SPATA2 …