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TRIM2 E3 ligase substrate discovery reveals zinc-mediated regulation of TMEM106B in the endolysosomal pathway

Finally! After 8 hard years of working, mostly by Cecilia Perez-Borrajero, our work on TRIM2/TMEM106B is published at EMBO Reports: https://link.springer.com/article/10.1038/s44319-025-00667-3.

We could show by proximity labeling and quantitative mass spectrometry that TRIM2 is the E3 ligase, which ubiquitinates TMEM106 among other targets. TMEM106B, a membrane protein, which often resides in the lysosomal membrane is monoubiquitinated by TRIM2. For this, the formation of a novel Zn-mediated dimerization motif in the cytosolic region of TMEM106B, formerly thought to be entirely disordered, is targeted by TRIM2. Mutation of the cysteines coordinating Zn leads to failure to dimerize in vitro and in vivo with consequences for lysosome assembly.

Thanks to our collaborators Sagar Bhogaraju, Misha Savitski, Kyung-Min Noh and Julia Mahamid at EMBL.