The ups and downs of STAT3 function: too much, too little and human immune dysregulation

Summary 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 in...

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Published in:Clinical and experimental immunology 2023-04, Vol.212 (2), p.107-116
Main Authors: Mackie, Joseph, Ma, Cindy S, Tangye, Stuart G, Guerin, Antoine
Format: Article
Language:English
Subjects:
Autoimmunity - genetics
Autoimmunity - immunology
Humans
Immune System Diseases - genetics
Immune System Diseases - immunology
Immunity - genetics
Immunity - immunology
Mutation - genetics
Review Series: Inborn errors of Immunity: The Goldilocks effect Series Editors: Cindy S Ma & Stuart G Tangye
STAT3 Transcription Factor - immunology
STAT3 Transcription Factor - metabolism
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Summary:Summary 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. Inborn errors of STAT3 immunity can result in diverse clinical phenotypes due to activating/gin of function or dominant negative/loss of function variants. These conditions manifest as immune dysregulation, as well as non-immune defects. Targeted therapies guided by genotype can improve patient outcomes. Graphical Abstract Graphical Abstract
ISSN:0009-9104
1365-2249
DOI:10.1093/cei/uxad007