Hsp27 and F-box protein β-TrCP promote degradation of mRNA decay factor AUF1

Area of Science:

• Molecular Biology
• Cell Signaling
• mRNA Metabolism

Background:

• Mitogen-activated protein (MAP) kinases p38 and MK2 activate heat shock protein 27 (Hsp27) phosphorylation.
• Phosphorylated Hsp27 stabilizes mRNAs with AU-rich elements (AREs) by promoting degradation of the decay factor AUF1.
• AUF1 is a key regulator of ARE-mRNA stability.

Purpose of the Study:

• To elucidate the molecular mechanism linking Hsp27 phosphorylation to AUF1 proteasomal degradation.
• To investigate the role of the E3 ubiquitin ligase β-TrCP in this process.
• To understand how this pathway impacts cytokine ARE-mRNA stability.

Main Methods:

• Investigated the interaction between Hsp27, AUF1, and β-TrCP.
• Utilized phosphomimetic mutant forms of Hsp27 and AUF1.
• Employed β-TrCP depletion and overexpression experiments.
• Assessed ubiquitination and proteasomal degradation of AUF1.
• Measured the stability of reporter mRNAs containing cytokine AREs.

Main Results:

• AUF1 is a substrate of the SCF(β-TrCP) E3 ubiquitin ligase.
• Depletion of β-TrCP stabilized AUF1.
• Overexpression of β-TrCP enhanced AUF1 ubiquitination and degradation.
• Enhanced AUF1 degradation and subsequent ARE-mRNA stabilization required phosphomimetic Hsp27 and AUF1.
• A signaling axis involving p38 MAP kinase, MK2, Hsp27, and β-TrCP was identified.

Conclusions:

• The p38 MAP kinase-MK2-Hsp27-β-TrCP signaling axis promotes AUF1 degradation via proteasomes.
• This pathway leads to the stabilization of cytokine ARE-mRNAs.
• Hsp27 phosphorylation is a critical step in regulating AUF1 stability and ARE-mRNA turnover.