Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification

Nature Cell Biology
Mümine ŞentürkHugo J Bellen

Abstract

Although the aetiology of amyotrophic lateral sclerosis (ALS) remains poorly understood, impaired proteostasis is a common feature of different forms of ALS. Mutations in genes encoding ubiquilins, UBQLN2 and UBQLN4, cause familial ALS. The role of ubiquilins in proteasomal degradation is well established, but their role in autophagy-lysosomal clearance is poorly defined. Here, we describe a crosstalk between endoplasmic reticulum stress, mTOR signalling and autophagic flux in Drosophila and mammalian cells lacking ubiquilins. We found that loss of ubiquilins leads to endoplasmic reticulum stress, impairs mTORC1 activity, promotes autophagy and causes the demise of neurons. We show that ubiquilin mutants display defective autophagic flux due to reduced lysosome acidification. Ubiquilins are required to maintain proper levels of the V0a/V100 subunit of the vacuolar H+-ATPase and lysosomal pH. Feeding flies acidic nanoparticles alleviates defective autophagic flux in ubiquilin mutants. Hence, our studies reveal a conserved role for ubiquilins as regulators of autophagy by controlling vacuolar H+-ATPase activity and mTOR signalling.

References

Sep 20, 2000·The Journal of Cell Biology·Y KamadaY Ohsumi
Nov 19, 2003·Neuron·Patrik VerstrekenHugo J Bellen
May 22, 2004·BioTechniques·Dennis Richard LaJeunesseKathryn Fromson
Aug 7, 2004·Developmental Cell·Ryan C ScottThomas P Neufeld
Jul 22, 2006·Pharmaceutical Research·Hyun Jung ChungTae Gwan Park
Oct 13, 2006·Molecular and Cellular Biology·Maiko OgataKazunori Imaizumi
Jul 7, 2007·Cell Death and Differentiation·M Høyer-Hansen, M Jäättelä
Jul 31, 2007·Advanced Drug Delivery Reviews·Lisa M Bareford, Peter W Swaan
Mar 1, 2008·Biochemical and Biophysical Research Communications·Tae-Yeon KimJong-Bok Yoon
Apr 3, 2009·The EMBO Journal·César S MendesBertrand Mollereau
May 26, 2009·Nature Methods·Koen J T VenkenRoger A Hoskins
Oct 13, 2009·Current Biology : CB·Donna DentonSharad Kumar
Oct 14, 2009·The Journal of Cell Biology·Precious J LimMervyn J Monteiro
Jun 10, 2010·Human Molecular Genetics·Cara RothenbergMervyn J Monteiro
Feb 24, 2011·Science Signaling·Chien-Hung ChenDos D Sarbassov
Mar 27, 2012·Trends in Cell Biology·Christian Appenzeller-Herzog, Michael N Hall
Nov 26, 2013·Human Molecular Genetics·Amina Moustaqim-BarretteHiroshi Tsuda
Dec 26, 2013·Human Molecular Genetics·Lijun WangRaymond P Roos
Sep 27, 2014·Genome Research·Nele A HaeltermanHugo J Bellen
Feb 7, 2015·Trends in Biochemical Sciences·Daniela Senft, Ze'ev A Ronai
May 12, 2015·Nature Communications·Caroline MauvezinThomas P Neufeld
Jun 30, 2015·Molecular Cell·Esperanza AriasAna María Cuervo
Sep 22, 2015·Autophagy·Harun-Or RashidHan-Jung Chae
Jun 25, 2016·Acta Neuropathologica Communications·Amit K ChouhanJoshua M Shulman
Jun 28, 2016·Molecular Cell·Eisuke ItakuraRamanujan S Hegde

❮ Previous
Next ❯

Citations

Nov 16, 2019·Science·Christian Pohl, Ivan Dikic
Mar 13, 2020·Journal of Virology·Xiaofang Liu, Billy Tsai
Mar 19, 2020·Molecular Biology of the Cell·Nigel W GriffithsJulie A Brill
Jun 10, 2020·International Journal of Molecular Sciences·Fiona LimanaqiFrancesco Fornai
Jun 19, 2020·Cancers·Salinee JantrapiromWutigri Nimlamool
Sep 24, 2020·The Biochemical Journal·Tongyin ZhengCarlos A Castañeda
Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Josephine J WuMervyn J Monteiro
May 14, 2020·International Journal of Molecular Sciences·Hyungsun ParkSeongju Lee
Jul 7, 2020·Autophagy·Julia Sanchez-Garrido, Avinash R Shenoy
May 8, 2020·Cell Discovery·Eleanna StamatakouDavid Chaim Rubinsztein
Sep 10, 2020·Frontiers in Neuroscience·Nicholas G Norwitz, Henry Querfurth
Apr 10, 2020·Nature·Siamak RedhaiIrene Miguel-Aliaga
Apr 30, 2020·International Journal of Molecular Sciences·Fiona LimanaqiFrancesco Fornai
Nov 3, 2020·The FEBS Journal·Harvey E Johnston, Rahul S Samant
Dec 17, 2020·American Journal of Physiology. Cell Physiology·Amity F EatonDennis Brown
Dec 11, 2020·ELife·Kathleen M CunninghamThomas E Lloyd
Dec 6, 2020·The Journal of Biological Chemistry·Alexandra M WhiteleyDaniel Finley
Sep 21, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Bin LiGuoyong Hu
Dec 20, 2020·Cellular and Molecular Life Sciences : CMLS·Enrico CastroflorioPeter L Oliver
Jan 6, 2021·Cell Death and Differentiation·Franziska OttensThorsten Hoppe
Jan 13, 2021·Scientific Reports·Julia E GersonMagdalena I Ivanova
Feb 24, 2021·Protein Science : a Publication of the Protein Society·Michelle Y FryWilliam M Clemons
Mar 5, 2021·Autophagy·Ruoxi ZhangDaolin Tang
Feb 22, 2021·Ecotoxicology and Environmental Safety·Quanwei LiZhaoxin Tang
Feb 27, 2021·Frontiers in Aging Neuroscience·Jaione Auzmendi-Iriarte, Ander Matheu
Apr 5, 2021·Experimental Cell Research·Masamitsu YamaguchiHideki Yoshida
May 6, 2021·Cell Discovery·Eleanna StamatakouDavid Chaim Rubinsztein
Jun 1, 2021·Autophagy·Jason P ChuaSami J Barmada
Jul 18, 2021·The FEBS Journal·Brian C LinMervyn J Monteiro
Jul 26, 2021·The Journal of Biological Chemistry·Nathaniel SafrenSami J Barmada
Aug 28, 2021·International Journal of Molecular Sciences·Amy KimJoana Gil-Mohapel
Mar 8, 2020·Journal of Molecular Biology·Frédéric Darios, Giovanni Stevanin
Oct 16, 2021·Frontiers in Endocrinology·Carolin MuleyAlexander Bartelt

❮ Previous
Next ❯

Methods Mentioned

BETA
transmission electron microscopy
immunoprecipitation
transgenic
dissection
lipidation
co-immunoprecipitation
PCR
ubiquitination
transfection
Protein Assay

Software Mentioned

Proteome Discoverer
Mascot
Xcalibur
Iontrap

Related Concepts

Related Feeds

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Amyloid Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.