The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes

Human Molecular Genetics
Markus M RinschenThomas Benzing

Abstract

The PHB-domain protein podocin maintains the renal filtration barrier and its mutation is an important cause of hereditary nephrotic syndrome. Podocin and its Caenorhabditis elegans orthologue MEC-2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the podocyte slit diaphragm, MEC-2 is found in neurons required for touch sensitivity. Here, we show that the ubiquitin ligase Ubr4 is a key component of the podocin interactome purified both from cultured podocytes and native glomeruli. It colocalizes with podocin and regulates its stability. In C. elegans, this process is conserved. Here, Ubr4 is responsible for the degradation of mislocalized MEC-2 multimers. Ubiquitylomic analysis of mouse glomeruli revealed that podocin is ubiquitylated at two lysine residues. These sites were Ubr4-dependent and were conserved across species. Molecular dynamics simulations revealed that ubiquitylation of one site, K301, do not only target podocin/MEC-2 for proteasomal degradation, but may also affect stability and disassembly of the multimeric complex. We suggest that Ubr4 is a key regulator of podocyte foot process proteostasis.

References

Mar 1, 1981·Developmental Biology·M Chalfie, J Sulston
Nov 13, 1999·Nature Cell Biology·B C BraunM Schmidt
Apr 20, 2001·Proceedings of the National Academy of Sciences of the United States of America·V G TusherG Chu
Mar 5, 2002·Nature·Miriam B GoodmanMartin Chalfie
Sep 6, 2002·The American Journal of Pathology·Minoru TakemotoChrister Betsholtz
Dec 31, 2002·Physiological Reviews·Hermann PavenstädtMatthias Kretzler
May 22, 2004·Journal of the American Society of Nephrology : JASN·Thomas Benzing
Oct 7, 2004·The American Journal of Pathology·Sian V GriffinStuart J Shankland
Feb 25, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Kah Leong LimTed M Dawson
Aug 2, 2005·Molecular and Cellular Biology·Takafumi TasakiYong Tae Kwon
Oct 11, 2005·Proceedings of the National Academy of Sciences of the United States of America·Yoshihiro NakataniAnna M Herlitz
Nov 3, 2006·Proceedings of the National Academy of Sciences of the United States of America·Tobias B HuberThomas Benzing
Jun 16, 2007·Nephron. Experimental Nephrology·Tobias B HuberThomas Benzing
Jan 29, 2008·Nature Structural & Molecular Biology·Andreas MartinRobert T Sauer
Mar 4, 2008·Nature Medicine·Thiruvur NiranjanKatalin Susztak
Jul 4, 2008·Journal of the American Society of Nephrology : JASN·Takamoto OhseStuart J Shankland
Jan 3, 2009·Nature Nanotechnology
May 16, 2009·Journal of Computational Chemistry·B R BrooksM Karplus
Sep 5, 2009·The Journal of Clinical Investigation·Paul T BrinkkoetterStuart J Shankland
Dec 25, 2009·Biological Chemistry·Vanja Nagy, Ivan Dikic
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Tzachi Hagai, Yaakov Levy
May 12, 2010·The Journal of Biological Chemistry·Irini TossidouMario Schiffer
Oct 5, 2010·Cell Metabolism·Gavin I WelshRichard J M Coward
Dec 28, 2010·Methods : a Companion to Methods in Enzymology·Nina C Hubner, Matthias Mann
Jun 7, 2011·Molecular & Cellular Proteomics : MCP·Annette MichalskiStevan Horning
Jul 27, 2011·PloS One·Fran SupekTomislav Šmuc
Jun 30, 2012·Nature Methods·Johannes SchindelinAlbert Cardona
Jul 14, 2012·Molecular & Cellular Proteomics : MCP·Sebastian A WagnerChunaram Choudhary
Aug 2, 2012·The EMBO Journal·Janko BrandOliver Daumke
Aug 3, 2012·The Journal of Chemical Physics·Xiongwu WuBernard R Brooks
Aug 30, 2012·Nature Methods·Caroline A SchneiderKevin W Eliceiri
Feb 1, 2013·Kidney International·Melanie BoerriesTobias B Huber
Feb 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Takafumi TasakiYong Tae Kwon

❮ Previous
Next ❯

Citations

Apr 13, 2017·Science Signaling·Markus M RinschenBernhard Schermer
Feb 1, 2018·The Journal of Biological Chemistry·Maria-Carmen Serrano-PerezGéraldine Mollet
Jul 1, 2016·American Journal of Physiology. Cell Physiology·Markus M RinschenPaul T Brinkkoetter
Apr 26, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Christina B SchroeterMarkus M Rinschen
Jul 21, 2017·Journal of the American Society of Nephrology : JASN·Markus M RinschenThomas Benzing
May 1, 2019·Nature Reviews. Nephrology·Catherine Meyer-Schwesinger
Sep 8, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Henning HagmannPaul T Brinkkoetter
May 10, 2017·Cell and Tissue Research·Athina Ganner, Elke Neumann-Haefelin
Jul 31, 2018·Frontiers in Pediatrics·Henning Hagmann, Paul T Brinkkoetter
Jul 25, 2019·Proceedings of the National Academy of Sciences of the United States of America·Artem MelnykovAlexander Varshavsky
Feb 13, 2020·Journal of the American Society of Nephrology : JASN·Sybille KoehlerMarkus M Rinschen
Jul 25, 2018·Scientific Reports·Gisela G SlaatsChristine E Kurschat
Dec 14, 2019·BMC Pediatrics· GunadiAkhmad Makhmudi
Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Cheng DongJinrong Min
Sep 14, 2018·Evidence-based Complementary and Alternative Medicine : ECAM·Jun JiangGuoyuan Lu
Oct 1, 2019·American Journal of Physiology. Renal Physiology·Xiao-Yu LuHe-Ping Ma
May 6, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jang-Hyun OhAlexander Varshavsky
Dec 12, 2019·Science Signaling·Markus M RinschenGary Siuzdak
Oct 9, 2020·Nature Reviews. Nephrology·Markus M Rinschen, Julio Saez-Rodriguez
Dec 3, 2021·Journal of the American Society of Nephrology : JASN·Linus ButtThomas Benzing

❮ Previous
Next ❯

Related Concepts

Related Feeds

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
Tobias B HuberThomas Benzing
Journal of the American Society of Nephrology : JASN
Bernhard Schermer, Thomas Benzing
International Journal of Nephrology and Renovascular Disease
Hong LuWilliam D Lyman
© 2022 Meta ULC. All rights reserved