Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.

Department of Medical Biosciences Building 6M Umeå University 901 85 Umeå Sweden

ICCVS University of Gdańsk Science ul Wita Stwosza 63 80 308 Gdańsk Poland

Inserm UMR 1078 Université de Bretagne Occidentale Bretagne CHRU Brest 29200 Brest France

Inserm UMRS 1131 Institut de Génétique Moléculaire Université de Paris Hôpital St Louis F 75010 Paris France

Institut Gustave Roussy Université Paris Sud Unité 1015 département d'immunologie 114 rue Edouard Vaillant 94805 Villejuif France

RECAMO Masaryk Memorial Cancer Institute Zluty kopec 7 65653 Brno Czech Republic

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