Vijayaraj Swarna L, Feltham Rebecca, Rashidi Maryam, Frank Daniel, Liu Zhengyang, Simpson Daniel S, Ebert Gregor, Vince Angelina, Herold Marco J, Kueh Andrew, Pearson Jaclyn S, Dagley Laura F, Murphy James M, Webb Andrew I, Lawlor Kate E, Vince James E
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
Nat Commun. 2021 May 11;12(1):2713. doi: 10.1038/s41467-021-22979-3.
Interleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1β activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1β is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1β cleavage by caspase-1. IL-1β K133 is modified by ubiquitin and forms a salt bridge with IL-1β D129. Loss of IL-1β K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1β. Accordingly, Il1b mice have increased levels of precursor IL-1β upon inflammasome priming and increased production of bioactive IL-1β, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1β activity and safeguard against damaging inflammation.
白细胞介素-1β（IL-1β）在罕见的自身炎症性疾病以及多种其他炎症性疾病中，由炎性小体相关的半胱天冬酶-1激活。因此，必须对IL-1β的活性进行微调，以实现抗菌反应，同时限制附带损害。在此，我们表明前体IL-1β被蛋白酶体快速周转，这与其被K11连接、K63连接和K48连接的泛素链修饰有关。IL-1β的泛素化不仅是由炎性小体启动和激活刺激触发的降解信号，还限制了半胱天冬酶-1对IL-1β的切割。IL-1β的K133被泛素修饰，并与IL-1β的D129形成盐桥。IL-1β K133泛素化的缺失，或K133:D129静电相互作用的破坏，会使IL-1β稳定。相应地，在炎性小体启动后，Il1b小鼠的前体IL-1β水平升高，并且在体外以及对LPS注射的反应中，生物活性IL-1β的产生增加。这些发现确定了可以限制IL-1β活性并防止破坏性炎症的机制。
