TRAP1 AND THE PROTEASOME REGULATORY PARTICLE TBP7/Rpt3 INTERACT IN THE ENDOPLASMIC RETICULUM AND CONTROL CELLULAR UBIQUITINATION OF SPECIFIC MITOCHONDRIAL PROTEINS

Franca Esposito (1) , Maria Rosaria Amoroso (1) , Danilo Swann Matassa (1) , Gabriella Laudiero (1) , Anastasia Egorova (1) , Roman Polishchuk (1) , Francesca Maddalena (1) , Annamaria Piscazzi (1) , Corrado Garbi (1) , Matteo Landriscina (1) , Simona Paladino (1) , Daniela Sarnataro (1)

1 Department of Biochemistry and Medical Biotechnologies

TRAP1 is a mitochondrial antiapoptotic heat shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass spectrometry analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 co-localize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopy analyses, and directly interact, as confirmed by FRET analysis. This is the first demonstration of TRAP1 presence in this cellular compartment. TRAP1 silencing by shRNAs, in cells exposed to thapsigargin-induced ER stress, correlates with up-regulation of BiP/ Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, the expression of specific mitochondrial proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, since it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of ER-mitochondria crosstalk.

Mots clés: TRAP1; TBP7; mitochondria/ER crosstalk; protein quality control; ubiquitination

Domaines: Biologie cellulaire

Franca Esposito, Maria Rosaria Amoroso, Danilo Swann Matassa, Gabriella Laudiero, Anastasia Egorova, et al.. TRAP1 AND THE PROTEASOME REGULATORY PARTICLE TBP7/Rpt3 INTERACT IN THE ENDOPLASMIC RETICULUM AND CONTROL CELLULAR UBIQUITINATION OF SPECIFIC MITOCHONDRIAL PROTEINS. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.128⟩. ⟨hal-00686073⟩