Nuclear Lipid Droplets Exit to the Cytoplasm: A Novel Mechanism of non-nuclear pore-dependent material exchange

Abstract

In cellular biology, the extrusion of large molecular complexes from the nucleus has consistently represented a considerable challenge. In this investigation, we reveal a hitherto unexplored mechanism facilitating the efflux of nuclear lipid droplets (nLDs) from the nucleus directly into the cytoplasm, a process integral to comprehending cellular processes and nuclear dynamics. Through high-throughput sequencing, immunoprecipitation, and immunofluorescence experimentation, we demonstrated that the type I nucleoplasmic reticulum engages with nLDs, enabling the dynamic protein Rab8as transfer to the nLDs and fostering their translocation to the nuclear membrane. Phosphorylation of LMNA/C at the S392 site, adjacent to the nLD-nuclear membrane contact site, induces local depolymerization of lamins, creating an aperture that enables gradual nuclear exit of nLDs. Following this, nLDs, carrying DNA fragments, are released into the cytoplasm through budding and subsequently undergo autophagy-mediated degradation. Furthermore, we demonstrate that RhoA-PKC signaling enhances nLD movement and LMNA/C phosphorylation, while its inhibition impedes nuclear nLD efflux. Our groundbreaking investigation illuminates non-nuclear pore-dependent mechanisms of material exchange and offers fresh perspectives on nuclear metabolic pathways. In Brief O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/556761v1_ufig1.gif" ALT="Figure 1"> View larger version (107K): org.highwire.dtl.DTLVardef@38a213org.highwire.dtl.DTLVardef@1898caorg.highwire.dtl.DTLVardef@d7270forg.highwire.dtl.DTLVardef@14582a2_HPS_FORMAT_FIGEXP M_FIG C_FIG In this study, Jin et al. elucidate a novel mechanism for the expulsion of nuclear lipid droplets (nLDs) from the nucleus. They demonstrate that the activation of RhoA within the nucleus recruits Rab8a to the surface of nLDs. Concurrently, PKC phosphorylation triggers the phosphorylation of LMNA/C at the S392 site, leading to a localized depolymerization of lamins. This creates an aperture that allows for the gradual exit of nLDs from the nucleus. The efflux process of nLDs involves three sequential steps: rupture of the nuclear fibril layer, fusion of nLDs with the inner nuclear membrane (INM), and subsequent fusion with the outer nuclear membrane (ONM). This enables nLDs to enter the cytoplasm, shedding light on a previously unknown process of large molecular entity expulsion from the nucleus.