The nuclear-cytoskeleton connection influences many aspects of cellular architecture, including, nuclear positioning, the stiffness of the global cytoskeleton, and mechanotransduction. Central to all of these processes is the assembly and function of conserved SUN-KASH bridges, or LINC complexes, that span the nuclear envelope. Recent studies provide details of the higher order assembly and targeting of SUN proteins to the inner nuclear membrane. Structural studies characterize SUN-KASH interactions that form the central link of the nuclear-envelope bridge. KASH proteins at the outer nuclear membrane link the nuclear envelope to the cytoskeleton where forces are generated to move nuclei. Significantly, SUN proteins were recently shown to contribute to the progression of laminopathies.

SUMMARYObservations from nematodes to mammals indicate that insulin/insulin-like growth factor signaling (IIS) regulates lifespan. As in other organisms, IIS is conserved in mosquitoes and signaling occurs in multiple tissues. During bloodfeeding, mosquitoes ingest human insulin. This simple observation suggested that exogenous insulin could mimic the endogenous hormonal control of aging in mosquitoes, providing a new model to examine this phenomenon at the organismal and cellular levels. To this end, female Anopheles stephensi mosquitoes were maintained on diets containing human insulin provided daily in sucrose or three times weekly by artificial bloodmeal. Regardless of delivery route, mosquitoes provided with insulin at 1.7ϫ10 -4 and 1.7ϫ10 -3 ·mol·l -1 , doses 0.3-fold and 3.0-fold higher than non-fasting blood levels, died at a faster rate than controls. In mammals, IIS induces the synthesis of reactive oxygen species and downregulates antioxidants, events that increase oxidative stress and that have been associated with reduced lifespan. Insulin treatment of mosquito cells in vitro induced hydrogen peroxide synthesis while dietary supplementation reduced total superoxide dismutase (SOD) activity and manganese SOD activity relative to controls. The effects of insulin on mortality were reversed when diets were supplemented with manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a cell-permeable SOD mimetic agent, suggesting that insulin-induced mortality was due to oxidative stress. In addition, dietary insulin activated Akt/protein kinase B and extracellular signal-regulated kinase (ERK) in the mosquito midgut, suggesting that, as observed in Caenorhabditis elegans, the midgut may act as a ʻsignaling centerʼ for mosquito aging.

The nucleoplasmic domain of the Caenorhabditis elegans SUN protein UNC-84 interacts with lamin. If this interaction is disrupted, a partial failure in nuclear migration occurs.

The mechanisms of inner nuclear membrane protein trafficking remain mostly unknown. We identified UNC-84 mutants that suggest that moving from the endoplasmic reticulum to the nuclear envelope does not occur by diffusion alone. Three signals need to be disrupted to block localization, suggesting that multiple mechanisms facilitate trafficking to the inner nuclear membrane.

SUN-KASH bridges that connect the nucleoskeleton to the cytoskeleton are only required to maintain nuclear envelope spacing in cells subjected to increased mechanical forces, such as muscle cells.

DNA repair is critical for genome integrity. Lawrence et al. reveal a role for a novel complex that links the nucleus to microtubules to promote accurate repair through both inhibition of error-prone nonhomologous end joining and promotion of homologous recombination.