Decreased mechanotransduction prevents nuclear collapse in a Caenorhabditis elegans laminopathy.

Gabriela Huelgas-Morales, Mark Sanders, Gemechu Mekonnen, Tatsuya Tsukamoto, David Greenstein

Proceedings of the National Academy of Sciences of the United States of America 2020 Dec 08

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The function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the nuclear envelope and mediates nuclear mechanotransduction, the process by which mechanical signals and forces are transmitted across the nuclear envelope. In turn, the AAA+ ATPase torsinA is thought to regulate force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia, though the extent to which endogenous mechanical stresses contribute to these pathologies is unclear. Here, we use the Caenorhabditis elegans germline as a model to investigate mechanisms that maintain nuclear integrity as germ cell nuclei progress through meiotic development and migrate for gametogenesis-processes that require LINC complex function. We report that decreasing the function of the C. elegans torsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog. We show that decreasing OOC-5/torsinA activity prevents nuclear collapse in lamin mutants by disrupting the function of the LINC complex. At a mechanistic level, OOC-5/torsinA promotes the assembly or maintenance of the lamin-associated LINC complex and this activity is also important for interphase nuclear pore complex insertion into growing germline nuclei. These results demonstrate that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina. Thus, the torsinA-LINC complex nexus might comprise a therapeutic target for certain laminopathies by preventing damage from endogenous cellular forces. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Gabriela Huelgas-Morales, Mark Sanders, Gemechu Mekonnen, Tatsuya Tsukamoto, David Greenstein. Decreased mechanotransduction prevents nuclear collapse in a Caenorhabditis elegans laminopathy. Proceedings of the National Academy of Sciences of the United States of America. 2020 Dec 08;117(49):31301-31308