Inflammasomes are multi-protein platforms that initiate innate immunity by recruitment and activation of Caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. Here we find that cleavage results in proteasome-mediated degradation of the N-terminal domains of NLRP1B, liberating a C-terminal fragment that is a potent Caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our “functional degradation” model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

Systematic analysis of related compounds is crucial to the design of single-molecule magnets with improved properties, yet such studies on multinuclear lanthanide complexes with strong magnetic coupling remain rare. Herein, we present the synthesis and magnetic characterization of the series of radical-bridged dilanthanide complex salts [(Cp*2Ln)2(μ-5,5′-R2bpym)](BPh4) (Ln = Gd, Dy; R = NMe2 (1), OEt (2), Me (3), F (4); bpym = 2,2′-bipyrimidine). Modification of the substituent on the bridging 5,5'-R2bpym radical anion allows the magnetic exchange coupling constant, JGd-rad, for the gadolinium compounds in this series to be tuned over a range from -2.7 cm -1 (1) to -11.1 cm -1 (4), with electron-withdrawing or -donating substituents increasing or decreasing the strength of exchange coupling, respectively. Modulation of the exchange coupling interaction has a significant impact on the magnetic relaxation dynamics of the single-molecule magnets 1-Dy through 4-Dy, where stronger JGd-rad for the corresponding Gd 3+ compounds is associated with larger thermal barriers to magnetic relaxation (Ueff), open magnetic hysteresis at higher temperatures, and slower magnetic relaxation rates for through-barrier processes. Further, we derive an empirical linear correlation between the experimental Ueff values for 1-Dy through 4-Dy and the magnitude of JGd-rad for the corresponding gadolinium derivatives that provides insight into the electronic structure of these complexes. This simple model applies to other organic radical-bridged dysprosium complexes in the literature, and it establishes clear design criteria for increasing magnetic operating temperatures in radical-bridged molecules.Synthesis and Structural Characterization. The molecule 2,2′-bipyrimidine (bpym) serves as an ubiquitous bridging ligand in coordination chemistry, however, symmetric 5,5′-R2bpym variants have only yet been reported for alkyl, aryl, ether, and bromine substituents. [35][36][37][38] Bipyrimidine derivatives are typically synthesized via Cu-or Ni-mediated coupling reactions, and therefore the synthesis of 5,5′-R2bpym was first attempted via a Ni-catalyzed homocoupling of the corresponding 5-R-2-chloropyrimidine. [39][40][41] This approach furnished 5,5′-R2bpym with electrondonating substituents R = Me, OEt, and NMe2 in isolated yields between 33 and 37% but did not yield electron-deficient derivatives with R = F or CF3. These results are consistent with reports of the synthesis of 5,5′-R2bpy (bpy = 2,2′-bipyridine), which found lower yields for the Ni-catalyzed homocoupling of 5-R-2-chloropyridine substrates bearing electron-withdrawing substituents. [42][43][44] Attempts to synthesize derivatives with R = F or CF3 via Cu-mediated homocoupling reactions were also unsuccessful. Instead, a Stille reaction 45,46 was used to couple 5-fluoro-2tributylstannylpyrimidine and 5-fluoro-2-chloropyrimidine, affording 5,5′-F2bpym in 57% isolated yield. Although it was not possible in our hands to isolate 5,5′-(CF3)2bpym by an analogous route, the Pd-catalyzed ...

Inflammasomes are multi-protein platforms that initiate innate immunity by recruitment and activation of Caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. Here we find that cleavage results in proteasomemediated degradation of the N-terminal domains of NLRP1B, liberating a C-terminal fragment 5 that is a potent Caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our new 'functional degradation' model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.