Torsin Mediates Primary Envelopment of Large Ribonucleoprotein Granules at the Nuclear Envelope

Vahbiz Jokhi,James Ashley,John Nunnari,Akiko Noma,Naoto Ito,Noriko Wakabayashi-Ito,Melissa J Moore,Vivian Budnik

doi:10.1016/j.celrep.2013.03.015

Abstract

A previously unrecognized mechanism through which large ribonucleoprotein (megaRNP) granules exit the nucleus is by budding through the nuclear envelope (NE). This mechanism is akin to the nuclear egress of herpes-type viruses and is essential for proper synapse development. However, the molecular machinery required to remodel the NE during this process is unknown. Here, we identify Torsin, an AAA-ATPase that in humans is linked to dystonia, as a major mediator of primary megaRNP envelopment during NE budding. In torsin mutants, megaRNPs accumulate within the perinuclear space, and the messenger RNAs contained within fail to reach synaptic sites, preventing normal synaptic protein synthesis and thus proper synaptic bouton development. These studies begin to establish the cellular machinery underlying the exit of megaRNPs via budding, offer an explanation for the "nuclear blebbing" phenotype found in dystonia models, and provide an important link between Torsin and the synaptic phenotypes observed in dystonia.

Highlights

Polarized assembly of cellular complexes often depends on formation of translationally silent RNA transport granules containing messenger RNAs (mRNAs) and associated structural and regulatory components
We recently uncovered a mechanism by which large ribonucleoprotein granules exit the nucleus via nuclear envelope (NE) budding (Speese et al, 2012), a mechanism previously shown to be utilized for the nuclear export of large herpes-type viral capsids (Maric et al, 2011; Mettenleiter et al, 2006)
In torsin mutants, including those mimicking genetic abnormalities in dystonia patients, mechanism through which large ribonucleoprotein (megaRNP) accumulate within the perinuclear space and the mRNAs contained within fail to reach synaptic sites, preventing normal synaptic protein synthesis and proper synaptic bouton development

Summary

SUMMARY

A previously unrecognized mechanism through which large ribonucleoprotein (megaRNP) granules exit the nucleus is by budding through the nuclear envelope (NE). MegaRNPs accumulate within the perinuclear space, and the messenger RNAs contained within fail to reach synaptic sites, preventing normal synaptic protein synthesis and proper synaptic bouton development. These studies begin to establish the cellular machinery underlying the exit of megaRNPs via budding, offer an explanation for the ‘‘nuclear blebbing’’ phenotype found in dystonia models, and provide an important link between Torsin and the synaptic phenotypes observed in dystonia

INTRODUCTION

RESULTS AND DISCUSSION

EXPERIMENTAL PROCEDURES