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TDP-43 was identified as the major component of ubiquitin and autophagosome-positive cytoplasmic inclusions in neurons in the large majority of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) patients. It has been shown that a loss of nuclear TDP-43 in combination with enhanced cytoplasmic mislocalization of TDP-43, which is associated with accumulation of TDP-43 aggregates in the cytosol, is an early and key event in TDP-43-mediated neurodegeneration. However, the mechanism underlying TDP-43 nucleocytoplasmic shuttling is still not clear. Here, we show that the tumor suppressor folliculin (FLCN) is a novel positive regulator of TDP-43 cytoplasmic translocation. FLCN directly interacts with TDP-43. The amino acids 202-299 of FLCN and RNA-recognition motif domains of TDP-43 are necessary for their interaction. In addition, both exogenous and endogenous FLCNs are required for TDP-43 cytoplasmic accumulation, protein aggregation and stress granule formation. Overall, our study suggests that FLCN may play an important role in the regulation of TDP-43 nucleocytoplasmic shuttling and TDP-43-mediated proteinopathy., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)