NLRP3 is an innate immune receptor that needs to be tightly regulated to prevent overshooting immune responses. Stutz et al. demonstrate that NLRP3 is phosphorylated as a safeguard against accidental activation, and that dephosphorylation involving PP2A activity is required for NLRP3 activation.

Highlights d Macrophages adopt a transient metabolic state in response to TLR4 activation d MyD88 and TRIF synergistically facilitate signaling-driven changes in metabolism d Increases in glycolysis and ATP-citrate lyase activity foster histone acetylation d ATP-citrate lyase governs gene induction of a distinct LPS responsive gene set

Roniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. Here, we show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas residence times on other CDKs are transient, thus giving rise to a kinetic selectivity of roniciclib. Surprisingly, variation of the substituent at the 5-position of the pyrimidine scaffold results in changes of up to 3 orders of magnitude of the drug-target residence time. CDK2 X-ray cocrystal structures have revealed a DFG-loop adaption for the 5-(trifluoromethyl) substituent, while for hydrogen and bromo substituents the DFG loop remains in its characteristic type I inhibitor position. In tumor cells, the prolonged residence times of roniciclib on CDK2 and CDK9 are reflected in a sustained inhibitory effect on retinoblastoma protein (RB) phosphorylation, indicating that the target residence time on CDK2 may contribute to sustained target engagement and antitumor efficacy.