Titel
HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation
Autor*in
Markus Schäfer
Research Institute of Molecular Pathology (IMP)
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Abstract
Tristetraprolin (TTP) is a critical negative immune regulator. It binds AU-rich elements in the untranslated-regions of many mRNAs encoding pro-inflammatory mediators, thereby accelerating their decay. A key but poorly understood mechanism of TTP regulation is its timely proteolytic removal: TTP is degraded by the proteasome through yet unidentified phosphorylation-controlled drivers. In this study, we set out to identify factors controlling TTP stability. Cellular assays showed that TTP is strongly lysine-ubiquitinated, which is required for its turnover. A genetic screen identified the ubiquitin E3 ligase HUWE1 as a strong regulator of TTP proteasomal degradation, which we found to control TTP stability indirectly by regulating its phosphorylation. Pharmacological assessment of multiple kinases revealed that HUWE1-regulated TTP phosphorylation and stability was independent of the previously characterized effects of MAPK-mediated S52/S178 phosphorylation. HUWE1 function was dependent on phosphatase and E3 ligase binding sites identified in the TTP C-terminus. Our findings indicate that while phosphorylation of S52/S178 is critical for TTP stabilization at earlier times after pro-inflammatory stimulation, phosphorylation of the TTP C-terminus controls its stability at later stages.
Stichwort
Research ArticleCell BiologyImmunology and Inflammationubiquitine3 ligasehuwe1tristetraprolininflammation
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
eLife
Band
12
ISSN
2050-084X
Erscheinungsdatum
2023
Publication
eLife Sciences Publications, Ltd
Projekt
Kod / Identifikator
P30231-B
Projekt
Kod / Identifikator
P30415-B
Projekt
Kod / Identifikator
F79
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Erscheinungsdatum
2023
Zugänglichkeit
Rechte
Rechteangabe
© 2023, Scinicariello et al
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