Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia.
Clin Exp Immunol. 2023 Apr 25;212(2):107-116. doi: 10.1093/cei/uxad007.
The STAT3 story has almost 30 years of evolving history. First identified in 1994 as a pro-inflammatory transcription factor, Signal Transducer and Activator of Transcription 3 (STAT3) has continued to be revealed as a quintessential pleiotropic signalling module spanning fields including infectious diseases, autoimmunity, vaccine responses, metabolism, and malignancy. In 2007, germline heterozygous dominant-negative loss-of-function variants in STAT3 were discovered as the most common cause for a triad of eczematoid dermatitis with recurrent skin and pulmonary infections, first described in 1966. This finding established that STAT3 plays a critical non-redundant role in immunity against some pathogens, as well as in the connective tissue, dental and musculoskeletal systems. Several years later, in 2014, heterozygous activating gain of function germline STAT3 variants were found to be causal for cases of early-onset multiorgan autoimmunity, thereby underpinning the notion that STAT3 function needed to be regulated to maintain immune homeostasis. As we and others continue to interrogate biochemical and cellular perturbations due to inborn errors in STAT3, we will review our current understanding of STAT3 function, mechanisms of disease pathogenesis, and future directions in this dynamic field.
STAT3 的故事已有近 30 年的发展历史。STAT3 最初于 1994 年被鉴定为一种促炎转录因子，随后不断被揭示为一种具有多功能的信号转导模块，涉及传染病、自身免疫、疫苗反应、代谢和恶性肿瘤等多个领域。2007 年，在 STAT3 中发现了种系杂合显性负性功能丧失变异，这是 1966 年首次描述的三联征湿疹性皮炎伴复发性皮肤和肺部感染的最常见原因。这一发现确立了 STAT3 在对抗某些病原体以及结缔组织、牙齿和肌肉骨骼系统的免疫中起着至关重要的非冗余作用。几年后，在 2014 年，种系激活功能获得性 STAT3 变异被发现是早发性多器官自身免疫病例的病因，从而支持了 STAT3 功能需要调节以维持免疫稳态的观点。随着我们和其他人继续研究 STAT3 中先天错误导致的生化和细胞扰动，我们将回顾我们对 STAT3 功能、疾病发病机制的机制以及这一动态领域未来方向的现有理解。
