Abstract：
The PYRIN inflammasome pathway is part of the innate immune response against invading pathogens. Unprovoked continuous activation of the PYRIN inflammasome drives autoinflammation and underlies several autoinflammatory diseases, including familial Mediterranean fever (FMF) syndrome. PYRIN inflammasome formation requires PYRIN dephosphorylation and oligomerization by molecular mechanisms that are poorly understood. Here, we use a functional genetics approach to find regulators of PYRIN inflammasome function. We identify the small Rho GTPase CDC42 to be essential for PYRIN activity and oligomerization of the inflammasome complex. While CDC42 catalytic activity enhances PYRIN phosphorylation, thereby inhibiting it, the inflammasome-supportive role of CDC42 is independent of its GDP/GTP binding or hydrolysis capacity and does not affect PYRIN dephosphorylation. These findings identify the dual role of CDC42 as a regulator of PYRIN and as a critical player required for PYRIN inflammasome assembly in health and disease.
摘要：
PYRIN炎性体途径是针对入侵病原体的先天免疫应答的一部分。PYRIN炎性体的无端持续激活导致自身炎症，并成为几种自身炎性疾病的基础。包括家族性地中海热（FMF）综合征。PYRIN炎性体形成需要PYRIN通过分子机制去磷酸化和寡聚化,但对其了解甚少。这里,我们使用功能遗传学方法来寻找PYRIN炎性体功能的调节因子。我们确定小RhoGTP酶CDC42对于PYRIN活性和炎性小体复合物的寡聚化至关重要。虽然CDC42催化活性增强PYRIN磷酸化，从而抑制它，CDC42的炎症小体支持作用与其GDP/GTP结合或水解能力无关,且不影响PYRIN去磷酸化。这些发现确定了CDC42作为PYRIN的调节因子和作为健康和疾病中PYRIN炎性体组装所需的关键参与者的双重作用。
