N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells.

Scientific Reports
Yu-Chuan ChenBegoña Diaz

Abstract

N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysos...Continue Reading

References

May 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·R J DuronioJ I Gordon
Jan 1, 1997·Cellular Signalling·J A Boutin
Apr 18, 1998·The Journal of Biological Chemistry·D K Giang, B F Cravatt
Mar 9, 2005·The Journal of Biological Chemistry·Shao H YangMartin O Bergo
Mar 11, 2005·Neurochemical Research·Yanjie LuRajendra K Sharma
Aug 27, 2005·Molecular Cancer Research : MCR·Charles E DuckerCharles D Smith
Feb 20, 2007·Journal of the American Chemical Society·Howard C HangHidde L Ploegh
Sep 3, 2008·Cell Metabolism·Thomas PorstmannAlmut Schulze
Feb 10, 2009·Methods in Enzymology·Geir BjørkøyTerje Johansen
Sep 15, 2009·Molecular Cell·Matteo BindaClaudio De Virgilio
Mar 13, 2010·The Journal of Pathology·Danielle GlickKay F Macleod
Jul 31, 2010·Molecular Cell·Katrin DüvelBrendan D Manning
Nov 9, 2010·Biochimie·Dale D O MartinLuc G Berthiaume
Oct 11, 2011·Molecular Cell·Angeles DuranMaria T Diaz-Meco
Jan 10, 2012·Biochemical and Biophysical Research Communications·Yusuke TakahashiMasato Okada
Jun 14, 2012·Science Signaling·Agnes Roczniak-FergusonShawn M Ferguson
Apr 24, 2013·Nature Reviews. Molecular Cell Biology·Carmine SettembreAndrea Ballabio
Sep 27, 2014·Nature Communications·Emmanuelle ThinonEdward W Tate
Feb 11, 2015·Annual Review of Physiology·Haoxing Xu, Dejian Ren
Oct 2, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Francesca RampoldiStefan Porubsky
Feb 28, 2016·Current Opinion in Cell Biology·Saara Hämälistö, Marja Jäättelä
Jun 15, 2016·Annual Review of Cell and Developmental Biology·Nina Raben, Rosa Puertollano
Aug 9, 2016·Annual Review of Cell and Developmental Biology·Rushika M Perera, Roberto Zoncu
Oct 13, 2016·Annual Review of Pharmacology and Toxicology·Shawn M Davidson, Matthew G Vander Heiden
Dec 27, 2016·Nature Medicine·Shawn M DavidsonMatthew G Vander Heiden
Mar 12, 2017·Cell·Robert A Saxton, David M Sabatini
May 1, 2017·Methods in Molecular Biology·Colin Fennelly, Ravi K Amaravadi
Sep 14, 2017·Cancer Discovery·Vito W RebeccaRavi K Amaravadi
Dec 14, 2017·Nature·Haijuan YangNikola P Pavletich
Apr 6, 2018·Nature Reviews. Molecular Cell Biology·Ivan Dikic, Zvulun Elazar

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Citations

Jun 8, 2021·Frontiers in Cell and Developmental Biology·Chee Wai Fhu, Azhar Ali

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Methods Mentioned

BETA
lipidation
myristoylation
nuclear translocation
transfection
fluorescence microscopy
electrophoresis
Assay

Software Mentioned

Zen Software
ImageScope Analysis
Aperio
GraphPad Prism
Adobe Photoshop
Zen Lite Software
Click
ImageJ

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