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Mapping Interactome Networks of DNAJC11, a Novel Mitochondrial Protein Causing Neuromuscular Pathology in Mice

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posted on 07.10.2019, 14:34 authored by Foteini Violitzi, Vasiliki-Iris Perivolidi, Trias Thireou, Ioannis Grivas, Sylva Haralambous, Martina Samiotaki, George Panayotou, Eleni Douni
We previously identified DNAJC11, a mitochondrial outer membrane protein of unknown function, as a novel genetic cause in modeled neuromuscular disease. To understand the physiological role of DNAJC11, we employed a proteomic approach for the identification of the DNAJC11 interactome, through the expression of DNAJC11-FLAG in HEK293FT cells and transgenic mice. Our analysis confirmed known DNAJC11-interacting proteins including members of the MICOS complex that organize mitochondrial cristae formation. Moreover, we identified in both biological systems novel mitochondrial interactions including VDACs that exchange metabolites across the outer mitochondrial membrane. In HEK293FT cells, DNAJC11 preferentially interacted with ribosomal subunits and chaperone proteins including Hsp70 members, possibly correlating DNAJC11 with cotranslational folding and import of mitochondrial proteins in metabolically active cells. Instead, the DNAJC11 interactome in the mouse cerebrum was enriched for synaptic proteins, supporting the importance of DNAJC11 in synapse and neuronal integrity. Moreover, we demonstrated that the DUF3395 domain is critically involved in DNAJC11 protein–protein interactions, while the J-domain determines its mitochondrial localization. Collectively, these results provide a functional characterization for DNAJC11 domains, while the identified interactome networks reveal an emerging role of DNAJC11 in mitochondrial biogenesis and response to microenvironment changes and requirements.

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