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Review
. 2023 Aug;43(6):1326-1359.
doi: 10.1007/s10875-023-01483-x. Epub 2023 May 4.

JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

Nils Ott  1 , Laura Faletti  2 , Maximilian Heeg  2   3 , Virginia Andreani  2 , Bodo Grimbacher  2   4   5   6   7
Affiliations
Review

JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

Nils Ott et al. J Clin Immunol. 2023 Aug.

Abstract

The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.

Keywords: Autoimmunity; Autoinflammation; Clinical phenotype; Gain-of-function mutations; Immunodeficiency; Inborn errors of immunity; JAK/STAT signaling pathway; JAK1; JAK3; Loss-of-function mutations; STAT1; STAT3; STAT6.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The traditional Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and its regulators. The activation of JAKs after cytokine stimulation results in the phosphorylation of STAT monomers or dimers, which then become activated, and translocate as dimers to the nucleus to activate gene transcription. Several proteins are involved in the regulation of the pathway: protein inhibitors of activated STATs (PIAS) can bind to STAT dimers and inhibit their DNA binding capacity, induce SUMOylation of STATs, or enhance the recruitment of other STAT co-repressors such as histone deacetylases (HDAC). Protein tyrosine phosphatases (PTPs) induce dephosphorylation of STATs and JAKs at various locations in the cell. Suppressors of cytokine signaling (SOCS) bind via their SH2 domain to phosphorylated tyrosine residues of JAKs, thereby inhibiting their kinase activity and the recruitment of STATs. In addition, they can activate other molecules such as Elongin B/C or Cul5, initiating an ubiquitylation cascade resulting in proteasomal degradation. ISG15 stabilizes USP18 which can disrupt the interaction of JAK and a cytokine receptor (IFNAR2). Created with BioRender.com
Fig. 2
Fig. 2
JAK/STAT signaling activity represented in different ways of understanding. A Traditionally, JAK/STAT signaling activity was understood as a spectrum. Herein, immune cells maintain the balance between the two possible extremes, immunodeficiency and autoinflammation/autoimmunity at a normal level. Loss-of-function or gain-of-function mutations of the various players can alter the balance, resulting in insufficient or exceeding JAK/STAT activity. B A deeper understanding of the pathomechanisms allows a more differentiated view of the diseases today. Immunodeficiency and autoimmunity symptoms are not mutually exclusive but may have shared molecular causes. JAK/STAT LOF and GOF diseases can therefore be represented two-dimensionally in a coordinate system with different intensities of the two symptom complexes. LOF, loss-of-function; GOF, gain-of-function; DN, dominant-negative. Created with BioRender.com
Fig. 3
Fig. 3
The traditional Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and molecular dysregulations. At a molecular level, a range of possible dysregulations can occur in JAK/STAT LOF and GOF diseases. Illustrated here are most of the molecular pathomechanisms that have been investigated to date for the respective syndromes. Defects of the pseudokinase domain of JAKs can occur, some of which may result in disruption of the phosphor-transfer function of JAK. Also, defects of STAT phosphorylation, dimerization, or binding of other STATs until their sequestration affect STAT activity. Furthermore, STAT dimers are known to get destabilized in their antiparallel conformation which can promote STAT dephosphorylation. Altered nuclear import and mobility can cause nuclear accumulation of active STAT dimers. Variations in DNA binding specificity, DNA binding affinity, epigenetic changes, and transcriptional activity eventually lead to increased, decreased, or non-specific expression of downstream target genes. Resulting altered SOCS expression with dysregulations of STATs is just one mechanism how JAK/STAT LOF and GOF can have a further effect. STAT isoform-specific dysregulations at the cellular level or their influence on further downstream pathways will be discussed in the corresponding sections. Downregulations are indicated in blue; upregulations are indicated in red. Created with BioRender.com
Fig. 4
Fig. 4
Overlapping phenotypes of JAK/STAT LOF and GOF diseases. Visual representation of the clinical phenotypes in JAK/STAT LOF and GOF diseases. Each disease can manifest with typical symptoms, which can affect different organ systems. Some syndromes show more overlapping symptoms than others. Symptoms can also occur in both LOF and GOF of the same protein, but also in LOF and GOF of different proteins. Rather immunodeficiency associated symptoms appear blue; rather autoimmunity associated symptoms appear red. STAT6 GOF symptoms are displayed in two boxes. LOF, loss-of-function; GOF, gain-of-function; IgE, Immunoglobulin E; IgA, immunoglobulin A; IgG, Immunoglobulin G; CMCD, chronic mucocutaneous candidiasis disease; SLE, systemic lupus erythematosus; CVID, common variable immunodeficiency; T-LGL, T cell large granular lymphocyte leukemia; SCID, severe combined immunodeficiency; AiKD, autoinflammation keratinization disease. Created with BioRender.com
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