The nascent polypeptide-associated complex (NAC) controls translation initiation in cis by recruiting nucleolin to...

Area of Science:

• Molecular Biology
• Virology
• Neuroscience

Background:

• Protein aggregates are linked to neurodegenerative diseases.
• Cells possess mechanisms to clear aggregates, but preventing synthesis of aggregate-prone proteins is less understood.
• The Epstein-Barr virus (EBV) protein EBNA1 suppresses its own translation to evade immune detection.

Purpose of the Study:

• To investigate how EBNA1 regulates its own synthesis.
• To elucidate the role of the glycine-alanine repeat (GAr) in EBNA1-mediated translation control.
• To identify cellular factors involved in this regulatory process.

Main Methods:

• Studied the interaction of EBNA1's GAr domain with the ribosome and associated factors.
• Investigated the role of the nascent polypeptide-associated complex (NAC) and nucleolin.
• Utilized mRNA binding assays and translation inhibition experiments.
• Manipulated NAC alpha (NACA) expression to assess its impact on GAr-mediated translation suppression.

Main Results:

• The emerging GAr peptide of EBNA1 dislodges NAC from the ribosome.
• This event leads to nucleolin recruitment to the GAr-encoding mRNA.
• Nucleolin binding suppresses mRNA translation initiation in cis.
• Suppression of NACA expression blocks nucleolin binding and overcomes GAr-mediated translation inhibition.

Conclusions:

• EBNA1 utilizes a nascent protein quality control pathway to regulate its synthesis rate.
• This pathway involves sensing the nascent GAr peptide by NAC.
• Subsequent recruitment of nucleolin to the GAr mRNA sequence controls translation.
• This mechanism allows EBNA1 to minimize the production of antigenic peptides for MHC class I presentation.