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Regulation of gene-activation pathways by PIAS proteins in the immune system

Nature Reviews Immunology volume 5, pages 593–605 (2005)Cite this article

Key Points

  • Protein inhibitor of activated STAT (signal transducer and activator of transcription protein) proteins (PIAS proteins) regulate the activity of certain transcription factors — such as STATs, nuclear factor-κB and SMADs (SMA (small body size)- and MAD (mothers against decapentaplegic)-related proteins) — in cytokine-mediated signalling, using distinct mechanisms.

  • PIAS proteins can inhibit transcription by blocking the DNA-binding activity of transcription factors.

  • PIAS proteins can negatively or positively regulate transcription by recruiting transcriptional co-regulators, such as histone deacetylases, or p300 or CBP (cyclic-AMP-responsive-element-binding protein (CREB)-binding protein), respectively.

  • PIAS proteins have SUMO (small ubiquitin-like modifier)-E3-ligase activity, which might be involved in transcriptional regulation.

  • PIAS1 has specific effects on cytokine-mediated signalling by selectively regulating a subset of interferon- or tumour-necrosis-factor-responsive genes.

  • PIAS1 is important in innate immunity. A deficiency in PIAS1 results in increased protection against viral and bacterial infection.

Abstract

The protein inhibitor of activated STAT (PIAS) family of proteins has been proposed to regulate the activity of many transcription factors, including signal transducer and activator of transcription proteins (STATs), nuclear factor-κB, SMA- and MAD-related proteins (SMADs), and the tumour-suppressor protein p53. PIAS proteins regulate transcription through several mechanisms, including blocking the DNA-binding activity of transcription factors, recruiting transcriptional corepressors or co-activators, and promoting protein sumoylation. Recent genetic studies support an in vivo function for PIAS proteins in the regulation of innate immune responses. In this article, we review the current understanding of the molecular basis, specificity and physiological roles of PIAS proteins in the regulation of gene-activation pathways in the immune system.

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Figure 1: The cytokine-activated STAT, NF-κB and SMAD pathways.
Figure 2: The domain structure of PIAS proteins.
Figure 3: Proposed mechanisms of PIAS-mediated transcriptional regulation.
Figure 4: The specificity of PIAS1-mediated transcriptional repression in STAT1 and NF-κB signalling.

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Acknowledgements

K.S. is supported by grants from the National Institutes of Health (United States). B.L. is a special fellow of The Leukemia & Lymphoma Society (United States).

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  1. Division of Hematology-Oncology, Department of Medicine, 11-934 Factor Building, 10833 Le Conte Avenue, University of California, Los Angeles, 90095, California, USA

    Ke Shuai & Bin Liu

  2. Department of Biological Chemistry, University of California, Los Angeles, 90095, California, USA

    Ke Shuai

Authors
  1. Ke Shuai
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  2. Bin Liu
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Correspondence to Ke Shuai.

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DATABASES

Entrez Gene

C/EBP-ε

MDM2

MITF

p50

p53

p65

p73

PIAS1

PIAS3

PIASx

PIASy

SATB2

SMAD2

SMAD3

SMAD4

STAT1

STAT3

STAT4

SUMO1

SUMO2

SUMO3

FURTHER INFORMATION

Ke Shuai's homepage

Glossary

SMALL-UBIQUITIN-LIKE-MODIFIER E3 LIGASE

(SUMO E3 ligase). An enzyme that catalyses the conjugation of SUMO to a protein substrate.

SCAFFOLD-ATTACHMENT REGION

(SAR). Also known as matrix-attachment region. A DNA element in the eukaryotic genome that attaches the chromatin fibre to the nuclear scaffold (which is also known as the nuclear matrix).

NUCLEAR SCAFFOLD

Also known as nuclear matrix. A subnuclear structure that consists of the proteinaceous network of the nuclues.

CHROMATIN-IMMUNOPRECIPITATION ASSAY

(ChIP assay). A technique for the detection of proteins bound to specific regions of chromatin. These assays involve chemically crosslinking bound proteins to the underlying DNA sequences, followed by immunoprecipitation with an antibody that is specific for the crosslinked protein.

NUCLEAR BODY

A subnuclear structure that is implicated in transcriptional repression, transcriptional activation and protein degradation.

MOBILITY GEL-SHIFT ANALYSIS

A technique to detect the DNA-binding activity of a protein in vitro. This assay involves the mixing of proteins with a specific DNA sequence, followed by the separation of this mixture by electrophoresis.

LUCIFERASE-REPORTER ASSAY

A method to measure the transcriptional response. This assay uses a promoter from a gene of interest fused to the gene that encodes luciferase.

YEAST THREE-HYBRID SCREEN

A system that is used to study ternary protein complexes. This technique involves three proteins that allow or prevent the formation of a functional transcriptional-activator complex.

MORPHOLINO OLIGONUCLEOTIDE

A 25-base-pair DNA analogue that operates by blocking mRNA translation or mRNA splicing and thereby inducing antisense effects. These oligonucleotides operate only when they are complementary either to a sequence that is located between the 5′ untranslated region and the first 25 bases 3′ of the AUG start site or to the sequence at a splice junction.

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Shuai, K., Liu, B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5, 593–605 (2005). https://doi.org/10.1038/nri1667

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  • DOI: https://doi.org/10.1038/nri1667

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