Abstract
Autophagy is a highly- evolutionarily-conserved catabolic pathway activated by various cellular stresses. Recently, non-canonical autophagy (NCA), which does not require all of the ATG proteins to form autophagosome or autophagosome-like structures, has been found in various conditions. Moreover, mounting evidence has indicated that non-canonical LC3 lipidation (NCLL) may reflect NCA. We and others have reported that niclosamide (Nic), an anti-helminthic drug approved by the Food and Drug Administration, could induce canonical autophagy via a feedback downregulation of mTOR complex 1. In this study, we found that Nic could also induce NCLL, which is independent of the ULK1 complex and Beclin 1 complex, but dependent on ubiquitin-like conjugation systems. Although bafilomycin A1 and concanamycin A, two known V-ATPase inhibitors, significantly inhibited Nic-induced NCLL, Nic-induced NCLL was demonstrated to be independent of V-ATPase. In addition, the Golgi complex and vimentin were involved in Nic-induced NCLL, which might be a platform or membrane source for Nic-induced LC3-positive structures. These results would be helpful to broaden our understanding of the working mechanisms of Nic and evaluate its pharmacological activities in diseases.
Highlights
Drug discovery and development are costly and lengthy processes
The ULK1 complex and Beclin 1 complex are essential for the early stage of autophagy
We found that Nic could still trigger LC3 lipidation in FIP200KO-mouse embryo fibroblast cells (MEFs), ULK1KO-MEFs, and Beclin 1KD-U251, cells as well as in wild-type MEFs (Figure 1A,B and Supplementary Figure S1G), whereas EBSS-induced canonical LC3 lipidation was abolished in these knockout/knockdown cells (Figure 1B and Supplementary Figure S1E,F)
Summary
Drug discovery and development are costly and lengthy processes. Drug repurposing has attracted increasing attention in recent years [1]. Drug repurposing means finding novel functions for existing drugs, which is more economical and faster than the canonical drug development strategy, as new uses of old drugs that have been well characterized and approved for human use could be evaluated rapidly in clinical trials [2]. Considerable studies have suggested that Nic is a multifunctional drug and has the potential to be a candidate for the treatment of various diseases [3]. One of its biological activities is to induce autophagy. We and others have demonstrated that Nic could induce canonical autophagy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
