Presentation description

The endoplasmic reticulum (ER) is an organelle that synthesizes lipids and proteins and also detects and resolves stress via the unfolded protein response (UPR) pathway through adaptive signaling. The nucleus, another important organelle, is surrounded by the nuclear envelope (NE) which protects the nucleus, regulates the genome, and determines the size and shape of the nucleus. These independently functioning organelles are physically connected, however, the extent to which the NE and ER impact each other's functions and structure is not well understood. Our lab has recently shown that the depletion of LEM2, a NE protein, results in lipid stress which activates the ATF6 branch of the UPR pathway in the ER. ATF6 activation upon LEM2 depletion consequently causes deformations in the nucleus, known as nuclear dysmorphia. Since cancer cells often display nuclear dysmorphia, I wanted to investigate how general the connection between NE proteins and the activation of the ATF6 pathway is. My research has shown that U2OS cells lacking Emerin, an NE protein in the same family as LEM2, results in nuclear dysmorphia via the ATF6 pathway while other branches of the UPR do not have an effect on nuclear shape. Future directions will expand on this work to identify mechanisms, such as which protein domains shared between LEM2 and Emerin prevent ATF6 activation and its disruption of nuclear architecture. To develop another tactic of assessing nuclear deformation, I cloned and transduced an NE marker, LBR(1-249)-GFP, into cell lines I constructed. In the future, live imaging of this new cell line will provide insight as to when and where nuclear deformation begins. Since nuclear dysmorphia is a hallmark of cancer, understanding the kinetics and mechanisms causing nuclear dysmorphia can jumpstart our research towards treating cancer.