Ctdnep1 and Eps8L2 regulate dorsal actin cables for nuclear positioning during cell migration

Abstract

Summary Cells actively position their nuclei within the cytoplasm for multiple cellular and physiological functions. 1 , 2 , 3 Consequently, nuclear mispositioning is usually associated with cell dysfunction and disease, from muscular disorders to cancer metastasis. 4 , 5 , 6 , 7 Different cell types position their nuclei away from the leading edge during cell migration. 8 , 9 , 10 , 11 In migrating fibroblasts, nuclear positioning is driven by an actin retrograde flow originated at the leading edge that drives dorsal actin cables away from the leading edge. The dorsal actin cables connect to the nuclear envelope by the linker of nucleoskeleton and cytoskeleton (LINC) complex on transmembrane actin-associated nuclear (TAN) lines. 12 , 13 , 14 Dorsal actin cables are required for the formation of TAN lines. How dorsal actin cables are organized to promote TAN lines formation is unknown. Here, we report a role for Ctdnep1/Dullard, a nuclear envelope phosphatase, 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 and the actin regulator Eps8L2 23 , 24 , 25 on nuclear positioning and cell migration. We demonstrate that Ctdnep1 and Eps8L2 directly interact, and this interaction is important for nuclear positioning and cell migration. We also show that Ctdnep1 and Eps8L2 are involved in the formation and thickness of dorsal actin cables required for TAN lines engagement during nuclear movement. We propose that Ctdnep1-Eps8L2 interaction regulates dorsal actin cables for nuclear movement during cell migration.

B Cells Adapt Their Nuclear Morphology to Organize the Immune Synapse and Facilitate Antigen Extraction

“…We thus sought to determine the impact of nuclear morphology in cell reorganization during immune synapse formation of B cells. Nuclear morphology and positioning have been shown to regulate diverse cellular functions, including signaling, gene expression (18), DNA repair or genome distribution (19)(20)(21), as well as cell shape (22) and migration (23)(24)(25). Nuclear size, form and positioning rely on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex (26)(27)(28).…”

A membrane sensing mechanism couples local lipid metabolism to protein degradation at the inner nuclear membrane

“…These processes may require maintenance of the INM lipid environment by CTDNEP1. Our work links INM lipids to Sun2 levels, thus providing a plausible explanation for why CTDNEP1 is necessary for nuclear positioning via the actin cytoskeleton (Calero-Cuenca et al, 2021) in which Sun2 is also required (Luxton et al, 2010; Zhu et al, 2017). Interestingly, Nem1, the CTDNEP1 homologue in budding yeast, genetically interacts with Mps3, a yeast SUN-domain protein, and mutations in mps3 result in altered lipid metabolism (Friederichs et al, 2012; Friederichs et al, 2011).…”

“…Our data combined with the work of others show that the INM harbors a unique lipid composition across multiple organisms. A common theme is a role for CTDNEP1 in NE-dependent processes including NE sealing, NPC biogenesis, nuclear size regulation, NE breakdown, and nuclear positioning (Bahmanyar et al, 2014; Calero-Cuenca et al, 2021; Jacquemyn et al, 2021; Mall et al, 2012; Mauro et al, 2021; Penfield et al, 2020). These processes may require maintenance of the INM lipid environment by CTDNEP1.…”

Dynamic regulation of LINC complex composition and function across tissues and contexts

“…Interestingly, the actin regulator Eps8L2 associates with CTDNEP1 to regulate LINC complexes residing in so‐called transmembrane actin‐associated nuclear ‘TAN lines’ [44], hinting that mechanical information from the actomyosin cytoskeleton could influence CTDNEP1‐dependent regulation of SUN2 protein stability, which in turn could reinforce LINC complexes; this attractive model has yet to be explored. In addition, it is worth noting that rapid cyclic stretch increases SUN2 phosphorylation at Ser21 [39], which resides in the ‘Site 1’ SCF βTrCP ‐binding motifs that can positively affect SUN2 turnover as described by Carvalho and colleagues [41].…”