HuR and Nuclear Envelope Proteins in Cell Fate Regulation

Apoptosis and senescence are cell death key processes. Senescence has also been shown to play important roles in promoting cancer through the secretion of senescence associated factors. The mitochondria are a key organelle that contribute to senescence and apoptosis. Proteins that are mistargeted to the mitochondria, while usually cleared by the quality control machinery, can impose stress on the mitochondria and affect mitochondrial functions when they are not cleared. We found that a nuclear envelope L353Q KASH5 variant localizes to the mitochondria. This mislocalization had no obvious effect on the mitochondrial membrane potential, but it had a statistically significant effect mitochondrial spare respiratory capacity and ATP production.We next examined the role of the RNA binding protein HuR in apoptosis. HuR is known to regulate mRNAs of apoptosis related proteins. We found that chemoresistant MCF7 cells failed to cleave HuR in response to apoptotic stimuli. Upon reintroduction of HuR cleaved products, the potential for apoptosis was restored. HuR is a nuclear protein that translocates to the cytoplasm in a stress-induced manner. The cytoplasmic targeting is facilitated by nuclear pore complexes and the cytoskeleton. We examined the nuclear envelope protein Nesprin 4, a key contributor to cytoskeletal organization, for its role in HuR localization in breast cancer apoptosis. We found no direct interaction between HuR and Nesprin 4. However, we discovered a novel regulation of Lamin B1, another nuclear envelope protein, by HuR. Since both HuR and Lamin B1 are known to contribute to senescence independently, we investigated the HuR Lamin B1 regulation in the context of breast cancer senescence. We found that HuR regulates LMNB1 mRNA translation and HuR knockdown resulted in an increase in Lamin B1 protein expression.