Novel signal transducer and activator of transcription 1 mutation disrupts small ubiquitin-related modifier conjugation causing gain of function - 22/09/17
, Li Ding, MD a, Stacey R. Rose, MD b, ∗, Phillip Cruz, PhD c, Amy P. Hsu, BS a, Anuj Kashyap, BA a, Lindsey B. Rosen, BS a, Margery Smelkinson, PhD d, Tatyana A. Tavella, BS a, Elise M.N. Ferre, PA b, Meredith K. Wierman, DO e, Christa S. Zerbe, MD a, Michail S. Lionakis, MD, ScD b, Steven M. Holland, MD aCet article a été publié dans un numéro de la revue, cliquez ici pour y accéder
Abstract |
Background |
Sumoylation is a posttranslational reversible modification of cellular proteins through the conjugation of small ubiquitin-related modifier (SUMO) and comprises an important regulator of protein function.
Objective |
We sought to characterize the molecular mechanism of a novel mutation at the SUMO motif on signal transducer and activator of transcription 1 (STAT1).
Methods |
STAT1 sequencing and functional characterization were performed in transfection experiments by using immunoblotting and immunoprecipitation in STAT1-deficient cell lines. Transcriptional response and target gene activation were also investigated in PBMCs.
Results |
We identified a novel STAT1 mutation (c.2114A>T, p.E705V) within the SUMO motif (702IKTE705) in a patient with disseminated Rhodococcus species infection, Norwegian scabies, chronic mucocutaneous candidiasis, hypothyroidism, and esophageal squamous cell carcinoma. The mutation is located in the tail segment and is predicted to disrupt STAT1 sumoylation. Immunoprecipitation experiments performed in transfected cells confirmed absent STAT1 sumoylation for E705V, whereas it was present in wild-type (WT) STAT1 cells, as well as the loss-of-function mutants L706S and Y701C. Furthermore, stimulation with IFN-γ led to enhanced STAT1 phosphorylation, enhanced transcriptional activity, and target gene expression in the E705V-transfected compared with WT-transfected cells. Computer modeling of WT and mutant STAT1 molecules showed variations in the accessibility of the phosphorylation site Y701, which corresponded to the loss-of-function and gain-of-function variants.
Conclusion |
This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key posttranslational regulatory modification of STAT1 and identify a novel mechanism for gain-of-function STAT1 disease in human subjects.
Le texte complet de cet article est disponible en PDF.Key words : Signal transducer and activator of transcription 1, gain of function, sumoylation, small ubiquitin-related modifier, IFN-γ, Rhodococcus species infection
Abbreviations used : CMC, GFP, GOF, IP10, IRF, LOF, MD, PE, pSTAT1, SENP, STAT1, SUMO, WT
Plan
| Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN 261200800001E. |
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| Disclosure of potential conflict of interest: M. S. Lionakis's institution received grants from Viamet and Matinas BioPharma for other works. The rest of the authors declare that they have no relevant conflicts of interest. |
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