4-Hydroxy-2-nonenal causes nuclear accumulation of p62 by inhibiting Xpo1 and promoting the proteolytic pathway in the nucleus

p62, an adapter protein involved in selective autophagy, is mainly found in the cytoplasm under normal conditions. Because p62 has nuclear localization signal (NLS) and a nuclear export signal, it has been suggested that p62 shuttles between the nucleus and cytoplasm. We studied the effect of 4-hydroxy-nonenal (4-HNE), an endogenous lipid peroxidation product, on intracellular p62 distribution in mouse embryonic fibroblasts. We found that treatment of 4-HNE causes p62 translocation from the cytoplasm to the nucleus. Further analysis revealed that 4-HNE directly binds to exportin-1 (Xpo1), essential protein for nuclear export of various proteins. Further analysis 4-HNE enhanced intranuclear EGFP-NLS-CL1 degradation in a p62-dependent manner. Our results suggest that 4-HNE changes p62 localization to the nucleus by inhibiting Xpo1 and might affect intranuclear protein quality control.