Nuclear Envelope Budding Enables Large Ribonucleoprotein Particle Export during Synaptic Wnt Signaling

Abstract

SUMMARY We report a novel mechanism of ribonucleoprotein (RNP) nucleocytoplasmic export by nuclear envelope budding. During development of Drosophila synapses, a fragment of the Wnt-1 receptor, DFrizzled2, is imported into postsynaptic nuclei where it forms prominent foci. We now show these foci to be composed of large RNP granules harboring synaptic protein transcripts. These RNPs exit the nucleus via a budding mechanism akin to nuclear egress of Herpes-type viruses, a process previously thought to be exclusive to these viruses. During this mechanism, RNP granules bud into the space between the inner and the outer nuclear membranes (the perinuclear space), in a manner dependent on Lamin C, a nuclear protein linked to muscular dystrophies. Like herpes virus nuclear egress, this process requires protein kinase C, which is known to disrupt the lamin through phosphorylation. We suggest that nuclear budding is an endogenous nuclear export pathway for large RNP granules.

Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication

“…Although nuclear egress was once thought to be limited to herpesviruses, recently, a broadly similar process has been identified for the export of ribonucleoprotein complexes in Drosophila (18,40), suggesting that insight into herpesvirus nuclear egress may be more generally applicable than previously thought. Still, the unusual structure presented here of a crucial player in nuclear egress underscores the unusual nature of this process.…”

“…These two proteins and their murine CMV (MCMV) homologues, M50 and M53, are essential for replication and nuclear egress (8,(14)(15)(16)(17) of their respective viruses. Although a process similar to herpesvirus nuclear egress was recently described for movement of ribonucleoprotein particles during Drosophila myogenesis (18), no host cell homolog of the NEC that would serve as mediator of this mechanism has yet been identified. Furthermore, no structural information currently exists for any NEC subunit across the Herpesviridae family.…”

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

“…Once through the lamina, capsids must traverse the nuclear membrane in a process now thought to be similar to the passage of large ribonucleoprotein particles from the nucleus to the cytoplasm (Jokhi et al, 2013;Speese et al, 2012). Briefly, capsids must bud through the inner leaflet of the nuclear membrane into the intramembrane space.…”

“…In HSV-infected cells, this process is governed by the interaction of the nuclear egress complex and capsid proteins (Yang & Baines, 2011). A similar mechanism may operate in HCMV-infected cells.Once through the lamina, capsids must traverse the nuclear membrane in a process now thought to be similar to the passage of large ribonucleoprotein particles from the nucleus to the cytoplasm (Jokhi et al, 2013;Speese et al, 2012). Briefly, capsids must bud through the inner leaflet of the nuclear membrane into the intramembrane space.…”

Expanding Proteostasis by Membrane Trafficking Networks

“…Indeed, the flexibility of TPN-based TRaCKS suggests that the plethora of emerging "unconventional" pathways may have a common framework that simply reflects the versatility of TPN function-and, thus, may not be so unconventional. These now include, for example, the genesis of autophagic membranes from the ER (Gee et al 2011;Deretic et al 2012) and the identification of multiple unanticipated compartment linkages including ER-phagosome (Hubber and Roy 2010;Huang et al 2011), ER-mitochondrial (Friedman et al 2011;Westermann 2011), Golgi-cell surface (Golgi-bypass) (Nickel 2010; Grieve and Rabouille 2011), ER-peroxisome (Lam et al 2011;Dimitrov et al 2013), preGolgi -endosome (Saraste et al 2009), and intranuclear-cytoplasmic trafficking pathways (Montpetit and Weis 2012;Speese et al 2012). In this regard, Golgi structure/function relationships have been a particularly acute area of controversy with many models (Morre and Ovtracht 1977;Emr et al 2009;Papanikou and Glick 2009;Pfeffer 2010;Glick and Luini 2011;Mironov and Beznoussenko 2011;Munro 2011b).…”