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Modulating Intra-Nuclear LC3 with Small Molecules Rescues Cells from an Aneuploidogen-Induced Phenotype
Rosenberg, Daniel P
Rosenberg, Daniel P
Abstract
Nuclear autophagy (nucleophagy) has been described as a cellular metabolic response by which nuclear material is actively degraded after stressors, such as nuclear damage or the onset of tumorigenesis. Here we describe nucleophagy as a process distinct from traditional macroautophagy in human cell lines. We found that although nuclear localization of LC3 is not dependent on particular nuclear importins, knockdown of nuclear importins (causing nuclear stress) can induce a nuclear autophagic response. Our characterization of nucleophagy was facilitated by chemical modulation of the process via two compounds discovered previously in a high content analysis. These small molecules bidirectionally regulate nuclear autophagy in human renal, pancreatic, and bladder cell lines. One molecule (NSC31762 or DTEP) enhances nuclear autophagic puncta and increases lysosomal targeting of LC3. Another molecule (NSC279895 or DIHI) reduces the nuclear localization of LC3. Finally, we applied these chemical tools in the setting of aneuploidy driven nuclear stress. The compound DIHI, shown to reduce nuclear autophagic puncta, was able to revert cells from aneuploidogen-induced phenotypes, possibly restoring homeostasis. These new tools will allow for a deeper exploration of nucleophagy, and could serve as proof-of-principle in guiding new therapies for diseases involving nuclear stress.
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2017-05-01
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Biology