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Vol. 20, Issue 3, 870-881, February 1, 2009

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The TP53INP2 Protein Is Required for Autophagy in Mammalian Cells

Jonathan Nowak^*, Cendrine Archange^*, Joël Tardivel-Lacombe^*, Pierre Pontarotti, Marie-Josèphe Pébusque^*, Maria Inés Vaccaro, Guillermo Velasco, Jean-Charles Dagorn^*, and Juan Lucio Iovanna^*

*Institut National de la Santé et de la Recherche Médicale U624, Stress Cellulaire, 13288 Marseille Cedex 9, France; Phylogenomics Laboratory, EA 3781 Evolution Biologique, Université de Provence, 13331 Marseille Cedex 03, France; School of Medicine, University of Buenos Aires, 1121 Buenos Aires, Argentina; and Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain

Submitted July 2, 2008; Revised October 28, 2008; Accepted November 20, 2008
Monitoring Editor: Jean E. Gruenberg

Using a bioinformatic approach, we identified a TP53INP1-related gene encoding a protein with 30% identity with tumor protein 53-induced nuclear protein 1 (TP53INP1), which was named TP53INP2. TP53INP1 and TP53INP2 sequences were found in several species ranging from Homo sapiens to Drosophila melanogaster, but orthologues were found neither in earlier eukaryotes nor in prokaryotes. To gain insight into the function of the TP53INP2 protein, we carried out a yeast two-hybrid screening that showed that TP53INP2 binds to the LC3-related proteins GABARAP and GABARAP-like2, and then we demonstrated by coimmunoprecipitation that TP53INP2 interacts with these proteins, as well as with LC3 and with the autophagosome transmembrane protein VMP1. TP53INP2 translocates from the nucleus to the autophagosome structures after activation of autophagy by rapamycin or starvation. Also, we showed that TP53INP2 expression is necessary for autophagosome development because its small interfering RNA-mediated knockdown strongly decreases sensitivity of mammalian cells to autophagy. Finally, we found that interactions between TP53INP2 and LC3 or the LC3-related proteins GABARAP and GABARAP-like2 require autophagy and are modulated by wortmannin as judged by bioluminescence resonance energy transfer assays. We suggest that TP53INP2 is a scaffold protein that recruits LC3 and/or LC3-related proteins to the autophagosome membrane by interacting with the transmembrane protein VMP1. It is concluded that TP53INP2 is a novel gene involved in the autophagy of mammalian cells.

Address correspondence to: Juan L Iovanna (iovanna{at}marseille.inserm.fr)

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