Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a

Abstract

Intracellular transport, processing and stability of mRNA play critical roles in the functional physiology of the cell and defects in these processes are thought to underlie the pathogenesis in a number of neurodegenerative disorders. One of the cellular sites that regulate the mRNA half-life is the processing bodies, the dynamic cytoplasmic structures that represent the non-translating mRNA and the ribonucleoprotein complex that also control the decapping and translation of mRNA. In the present study we explored the possible role of malin E3 ubiquitin ligase in the mRNA decay pathway via the processing bodies. Defects in malin are associated with Lafora disease (LD)—a neurodegenerative disorder characterized by myoclonus seizures. We show here that malin is recruited to the processing bodies and that malin regulates the recruitment of mRNA decapping enzyme Dcp1a by promoting its degradation via the ubiquitin proteasome system. Depletion of malin results in elevated levels of Dcp1a and an altered microRNA-mediated gene silencing activity. Our study suggests that malin is one of the critical regulators of processing bodies and that defects in the mRNA processing might underlie some of the disease symptoms in LD.

Keywords: :

• neurodegenerative disorder
• mRNA dysregulation
• epilepsy
• post-translational modification
• RNA granules
• stress response
• neuronal processing bodies

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Dr. Ken Fujimura, University of Tokyo, Japan, for providing us the RFP-tagged Dcp1a expression construct, Dr. Marvin J. Fritzler, University of Calgary, Canada, for the gift of GW182 antibody, Dr. Berge Minassian, Hospital for Sick Children, Canada, for the tissue lysates of the malin knockout mice, and Dr Amitabha Bandyopadhyay, IIT Kanpur, for extending his laboratory facilities. We also thank the anonymous reviewers for their comments and suggestions on an earlier version of this article. This work was supported by a sponsored research grant from the Department of Atomic Energy, Government of India, to S.G. S.G. is a Ramanna Fellow and Gill-Joy Chair Professor at IIT Kanpur. S.S. and P.K.S. were supported by a senior research fellowship from the Council of Scientific and Industrial Research, Government of India.

Supplemental Material

Supplemental material may be found here:

http://www.landesbioscience.com/journals/rnabiology/article/22708/