The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules

Area of Science:

• Molecular Biology
• Cell Biology
• Neuroscience

Background:

• RNA localization pathways are crucial for cellular function, directing mRNAs to specific subcellular locations.
• The adenomatous polyposis coli (APC) protein forms ribonucleoprotein complexes (RNPs) that target RNAs to cell protrusions.
• Mutations in the fused in sarcoma (Fus) protein are linked to amyotrophic lateral sclerosis (ALS) and the formation of cellular inclusions.

Purpose of the Study:

• To investigate the role of Fus/TLS in APC-RNP complex formation and function.
• To determine the impact of Fus on mRNA translation within cellular protrusions.
• To explore the relationship between Fus, stress granules, and RNA translation in the context of ALS.

Main Methods:

• Immunofluorescence microscopy to visualize APC-RNPs and Fus localization.
• Analysis of newly synthesized proteins using labeling techniques.
• Investigating the translational activity of RNA within Fus-containing granules.

Main Results:

• Fus/TLS associates with APC-RNPs but is not required for their localization to cell protrusions.
• Fus is essential for efficient translation of APC-RNP-associated transcripts, particularly within protrusions.
• Overexpression or mutation of Fus leads to the formation of cytoplasmic granules that recruit APC-RNPs.
• APC-RNP transcripts are actively translated within these Fus-containing granules, challenging the notion of stress granules as translationally silent.

Conclusions:

• Cytoplasmic Fus plays a critical role in promoting mRNA translation locally within cell protrusions.
• Stress-like granules formed by Fus are not translationally inert but can serve as sites for active RNA translation.
• These findings reveal a novel function for cytoplasmic Fus and have significant implications for understanding the pathogenesis of ALS.