Center for Inflammation, Immunity & Infection and Department of Biology, Georgia State University, Atlanta, 30303, USA.
Nat Commun. 2012 Apr 10;3:771. doi: 10.1038/ncomms1776.
Lung injury, whether induced by infection or caustic chemicals, initiates a series of complex wound-healing responses. If uncontrolled, these responses may lead to fibrotic lung diseases and loss of function. Thus, resolution of lung injury must be tightly regulated. The key regulatory proteins required for tightly controlling the resolution of lung injury have yet to be identified. Here we show that loss of deubiquitinase CYLD led to the development of lung fibrosis in mice after infection with Streptococcus pneumoniae. CYLD inhibited transforming growth factor-β-signalling and prevented lung fibrosis by decreasing the stability of Smad3 in an E3 ligase carboxy terminus of Hsc70-interacting protein-dependent manner. Moreover, CYLD decreases Smad3 stability by deubiquitinating K63-polyubiquitinated Akt. Together, our results unveil a role for CYLD in tightly regulating the resolution of lung injury and preventing fibrosis by deubiquitinating Akt. These studies may help develop new therapeutic strategies for preventing lung fibrosis.
肺损伤，无论是由感染还是腐蚀性化学物质引起的，都会引发一系列复杂的创伤愈合反应。如果不受控制，这些反应可能会导致纤维性肺疾病和功能丧失。因此，肺损伤的愈合必须受到严格控制。控制肺损伤愈合的关键调节蛋白仍有待确定。在这里，我们发现去泛素化酶 CYLD 的缺失会导致肺炎链球菌感染后的小鼠发生肺纤维化。CYLD 通过 E3 连接酶羧基末端与 Hsc70 相互作用蛋白依赖性方式降低 Smad3 的稳定性，从而抑制转化生长因子-β信号转导并防止肺纤维化。此外，CYLD 通过去泛素化 K63-多泛素化 Akt 降低 Smad3 的稳定性。总之，我们的研究结果揭示了 CYLD 通过去泛素化 Akt 来严格调节肺损伤愈合和防止纤维化的作用。这些研究可能有助于开发预防肺纤维化的新治疗策略。
