AKT constitutes a signal-promoted alternative exon-junction complex that regulates nonsense-mediated mRNA decay

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Nonsense-mediated mRNA decay (NMD) is a critical cellular surveillance pathway for degrading aberrant mRNAs.
• While NMD's role is established, additional regulatory factors in mammalian cells are continually being discovered.

Purpose of the Study:

• To identify novel effectors that regulate NMD activity in mammalian cells.
• To elucidate the mechanism by which these novel effectors modulate NMD.

Main Methods:

• Conducted a haploid-cell genetic screen to identify NMD regulators.
• Utilized induced pluripotent stem cells (iPSCs) derived from Fragile X syndrome patient models (FMR1-KO neural stem cells).

Main Results:

• Identified 13 proteins of the AKT signaling pathway as NMD effectors.
• Demonstrated that AKT phosphorylates UPF1 at T151, enhancing its helicase activity, which is essential for NMD.
• Showed AKT supersedes UPF2 in specific exon-junction complexes (EJCs).
• Linked AKT signaling upregulation to NMD hyperactivation in Fragile X syndrome models.

Conclusions:

• The AKT signaling pathway is an unanticipated regulator of NMD.
• AKT-mediated phosphorylation of UPF1 is a key mechanism controlling NMD efficiency.
• Dysregulated AKT signaling contributes to NMD hyperactivation in Fragile X syndrome.