The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2.
BACKGROUND
Lafora disease (LD, OMIM 254780) is a fatal neurodegenerative disorder produced mainly by mutations in two genes: EPM2A, encoding the dual specificity phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. Although it is known that laforin and malin may form a functional complex, the underlying molecular mechanisms of this pathology are still far from being understood.


METHODS
In order to gain information about the substrates of the laforin/malin complex, we have carried out a yeast substrate-trapping screening, originally designed to identify substrates of protein tyrosine phosphatases.


RESULTS
Our results identify the two muscular isoforms of pyruvate kinase (PKM1 and PKM2) as novel interaction partners of laforin.


CONCLUSIONS
We present evidence indicating that the laforin/malin complex is able to interact with and ubiquitinate both PKM1 and PKM2. This post-translational modification, although it does not affect the catalytic activity of PKM1, it impairs the nuclear localization of PKM2.
Instituto de Biomedicina de Valencia, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain. rviana@ibv.csic.es.
Rosa
R
Viana
Instituto de Biomedicina de Valencia, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain. pablo.lujan@embl.de.
Pablo
P
Lujan
Instituto de Biomedicina de Valencia, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain. sanz@ibv.csic.es.
Pascual
P
Sanz
D021581:Active Transport, Cell Nucleus; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000097810:Thyroid Hormone-Binding Proteins
D002352:Carrier Proteins; D008565:Membrane Proteins; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D013963:Thyroid Hormones; D044767:Ubiquitin-Protein Ligases; D000097810:Thyroid Hormone-Binding Proteins; C478960:NHLRC1 protein, human; C114990:EPM2A protein, human