Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease.

Journal of Cell Science
Brinda RavikumarDavid C Rubinsztein

Abstract

Huntington disease (HD) is caused by a polyglutamine-expansion mutation in huntingtin (HTT) that makes the protein toxic and aggregate-prone. The subcellular localisation of huntingtin and many of its interactors suggest a role in endocytosis, and recently it has been shown that huntingtin interacts indirectly with the early endosomal protein Rab5 through HAP40. Here we show that Rab5 inhibition enhanced polyglutamine toxicity, whereas Rab5 overexpression attenuated toxicity in our cell and fly models of HD. We tried to identify a mechanism for the Rab5 effects in our HD model systems, and our data suggest that Rab5 acts at an early stage of autophagosome formation in a macromolecular complex that contains beclin 1 (BECN1) and Vps34. Interestingly chemical or genetic inhibition of endocytosis also impeded macroautophagy, and enhanced aggregation and toxicity of mutant huntingtin. However, in contrast to Rab5, inhibition of endocytosis by various means suppressed autophagosome-lysosome fusion (the final step in the macroautophagy pathway) similar to bafilomycin A1. Thus, Rab5, which has previously been thought to be exclusively involved in endocytosis, has a new role in macroautophagy. We have previously shown that macroautophag...Continue Reading

References

Nov 1, 1971·Kybernetik·N Franceschini, K Kirschfeld
Aug 11, 1998·Nature·J M GaullierR Aasland
Dec 29, 1998·Biological Chemistry·A L KovácsP O Seglen
Oct 21, 1999·Journal of Medical Genetics·Y NarainD C Rubinsztein
Nov 13, 1999·Nature Cell Biology·S ChristoforidisM Zerial
Dec 22, 1999·Seminars in Cell & Developmental Biology·Y Argon, B B Simen
Dec 28, 1999·Annual Review of Cell and Developmental Biology·D J Klionsky, Y Ohsumi
Mar 27, 2001·The Journal of Cell Biology·N MizushimaT Yoshimori
Apr 5, 2002·Trends in Genetics : TIG·David C Rubinsztein
Apr 9, 2002·Cell Structure and Function·Atsuki NaraTamotsu Yoshimori
Apr 30, 2002·Human Molecular Genetics·Brinda RavikumarDavid C Rubinsztein
Feb 4, 2003·Nature Reviews. Molecular Cell Biology·Estela Jacinto, Michael N Hall
Mar 27, 2003·Traffic·Ayano SatohGraham Warren
Apr 30, 2003·The Journal of Biological Chemistry·Julie L WebbDavid C Rubinsztein
May 14, 2003·The Journal of Cell Biology·Tanja WucherpfennigMarcos González-Gaitán
Aug 17, 2005·The Journal of Cell Biology·Hye-Won ShinMarino Zerial
Sep 28, 2005·The Journal of Cell Biology·Sovan SarkarDavid C Rubinsztein
Dec 22, 2005·Human Molecular Genetics·Zdenek BergerDavid C Rubinsztein
Mar 9, 2006·The Journal of Biological Chemistry·Mamoru ShibataJunying Yuan
Jun 21, 2006·The Journal of Cell Biology·Krista M HennigThomas P Neufeld
Dec 22, 2006·The Journal of Biological Chemistry·Sovan SarkarDavid C Rubinsztein
Mar 31, 2007·Nature Reviews. Drug Discovery·David C RubinszteinDaniel J Klionsky

❮ Previous
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Citations

Jul 25, 2012·The Journal of Membrane Biology·Matthias M FalkAnastasia F Thévenin
Oct 16, 2009·Histochemistry and Cell Biology·Catherine Sem WegnerAndreas Brech
Apr 22, 2011·ACS Chemical Biology·Ke ZhanJianghong Rao
Nov 15, 2008·Cell Death and Differentiation·C M Fader, M I Colombo
Aug 29, 2009·Cell Death and Differentiation·S Luo, D C Rubinsztein
Apr 18, 2009·Cell Death and Differentiation·A Longatti, S A Tooze
May 21, 2013·Cell Death and Differentiation·V R VillellaL Maiuri
Jun 16, 2010·Cell Research·Maryam MehrpourPatrice Codogno
Jul 20, 2010·Nature Cell Biology·Brinda RavikumarDavid C Rubinsztein
Apr 13, 2010·Nature Neuroscience·Marta Martinez-VicenteAna Maria Cuervo
Feb 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Nadia JaberWei-Xing Zong
Nov 17, 2009·The Journal of Biological Chemistry·Wentao GaoXiao-Ming Yin
Jul 12, 2013·Cancer Biotherapy & Radiopharmaceuticals·Banzhou PanHaizhu Song
Aug 21, 2012·Carcinogenesis·Lisa B Frankel, Anders H Lund
Jun 11, 2011·Human Molecular Genetics·Mónica SanchoEnrique Pérez-Payá
Jan 21, 2010·The Journal of Pharmacology and Experimental Therapeutics·Komal M SaneRaymond R Mattingly
Mar 5, 2013·Physiology·Anastasia F ThéveninMatthias M Falk
Apr 8, 2009·Molecular Neurodegeneration·Philipp A Jaeger, Tony Wyss-Coray
May 23, 2009·Journal of Cell Science·Brinda RavikumarDavid C Rubinsztein
Apr 5, 2013·PLoS Genetics·Carmen I Nussbaum-KrammerRichard I Morimoto
Oct 17, 2012·PloS One·Lin QiZheng-Hong Qin
Mar 25, 2014·Journal of Neuroinflammation·Isabella RussoElisa Greggio
Dec 11, 2013·Acta Biochimica Et Biophysica Sinica·Lin Qi, Xing-Ding Zhang
Nov 28, 2013·International Journal of Cell Biology·Sybille Krauss, Ina Vorberg
Aug 28, 2012·Experimental Neurology·Jia-Yi Li, Laura Conforti
Jun 21, 2014·BioMed Research International·Nitha C MulakkalIoannis P Nezis
May 10, 2011·Annual Review of Biochemistry·Hilla WeidbergZvulun Elazar
Sep 15, 2012·Annual Review of Genetics·M JaiswalH J Bellen
Dec 3, 2014·Molecular and Cellular Neurosciences·Jia YaoSandra Bajjalieh
Feb 25, 2014·Translational Research : the Journal of Laboratory and Clinical Medicine·Mathieu F BakhoumGeorge R Jackson
Aug 22, 2014·Molecular Biology of the Cell·Yong ChenNava Segev
Aug 27, 2010·Seminars in Immunopathology·Chloe Burman, Nicholas T Ktistakis
Aug 28, 2010·Seminars in Immunopathology·Jonathan Zirin, Norbert Perrimon
Jun 21, 2011·Cellular and Molecular Life Sciences : CMLS·Christelle En Lin ChuaBor Luen Tang
Feb 4, 2014·FEBS Letters·Matthias M FalkViviana M Berthoud
Nov 12, 2013·Expert Opinion on Therapeutic Targets·Sharon L ChanEng-King Tan
Nov 10, 2010·The Journal of Cell Biology·Zhixun DouWei-Xing Zong
Aug 30, 2008·The Journal of Cell Biology·Anne Simonsen, Harald Stenmark
Sep 22, 2010·The Journal of Cell Biology·Ashley R WinslowDavid C Rubinsztein
Oct 3, 2009·The Journal of Cell Biology·Anne Simonsen, Sharon A Tooze
Dec 25, 2015·Nature Reviews. Rheumatology·Andras Perl

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