The intrinsically disordered protein TgIST from Toxoplasma gondii inhibits STAT1 signaling by blocking cofactor recruitment

Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes. The parasite Toxoplasma gondii blocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the...

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Vydané v:	Nature communications Ročník 13; číslo 1; s. 4047 - 15
Hlavní autori:	Huang, Zhou, Liu, Hejun, Nix, Jay, Xu, Rui, Knoverek, Catherine R., Bowman, Gregory R., Amarasinghe, Gaya K., Sibley, L. David
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 13.07.2022 Nature Publishing Group Nature Portfolio
Predmet:	101/58 13/109 13/31 14/5 631/250/2499 631/250/516 631/326/417/2547 631/535/1266 82/103 9/10 Antimicrobial responses BASIC BIOLOGICAL SCIENCES Binding Blocking Cell surface Cellular structure Dimerization Dimers Gene expression Genes Grooves Humanities and Social Sciences Immune response Immune system Interferon Interferon-gamma - metabolism Intrinsically Disordered Proteins - genetics Intrinsically Disordered Proteins - metabolism multidisciplinary Parasite immune evasion Parasites Phosphorylation Proteins Recruitment Science Science (multidisciplinary) Signal Transduction src Homology Domains Stat1 protein STAT1 Transcription Factor - metabolism Toxoplasma Toxoplasma gondii Transcription Transcription factors X-ray crystallography
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes. The parasite Toxoplasma gondii blocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectedly remain silenced. Here we define a core region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. Cellular, biochemical, mutational, and structural data demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. TgIST binding to this newly exposed site at the STAT1 dimer interface alters its conformation and prevents the recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription. Intrinsically disordered proteins (IDP) are pleotropic proteins with diverse functions. Here the authors show that an IDP, TgIST, from T. gondii blocks interferon-induced gene expression by binding to the STAT1 dimer interface and preventing the recruitment of co-transcriptional activators, CBP/p300, to STAT1 to inhibit expression of immunity genes.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 USDOE AC02-05CH11231; AI118426; P01AI120943 National Institutes of Health (NIH)
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-31720-7