Research Description

Biochemistry and function of the Nedd4 family of ubiquitin ligases

My laboratory has been studying the ubiquitin system, particularly the Nedd4 family of E3 ubiquitin ligases. We are studying the biochemistry, structure and function of these E3 ligases, as well as their physiological functions using cells and model organisms. Moreover, we have developed proteomic methodologies to globally identify substrates for E3 ubiquitin ligases and have subsequently focused our studies on some of the membrane proteins that were identified in these screens (eg the sodium channel ENaC, the FGF receptor, and several others). These studies are relevant to human diseases such as hypertension, cystic fibrosis (CF) and cancer.Other related project in the lab focus on two other membrane proteins: CFTR, the protein that is mutated in CF, for which we are developing assays and small molecules that can rescue the major mutation in this disease, and PTPsigma, a tyrosine phosphatase that malfunctions in Inflammatory Bowel Disease.

Publications

Ubiquitylation-dependent oligomerization regulates activity of Nedd4 ligases
Attali I, Tobelaim WS, Persaud A, Motamedchaboki K, Simpson-Lavy KJ, Mashahreh B, Levin-Kravets O, Keren-Kaplan T, Pilzer I, Kupiec M, Wiener R, Wolf DA, ROTIN D, Prag G
EMBO J. (2017) 36: 425-40

Drosophila Nedd4-long reduces Amphiphysin levels in muscles and leads to impaired T-tubule formation
Safi F, Shteiman-Kotler A, Zhong Y, Iliadi KG, Boulianne GL, ROTIN D
Mol. Biol. Cell (2016) 27: 907-918

System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes.
Zhang W, Wu K-P, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J*, ROTIN D*, Schulman BA*, Sidhu SS*. (*co-Senior authors)
Mol. Cell (2016) 62: 121-36

LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.
Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, ROTIN D.
Nat. Commun. (2015) 6: 7250: 1-9

RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR
Trzcinska-Daneluti AM, Chen A, Nguyen L, Murchie R, Jiang C, Moffat J, Pelletier L, ROTIN D.
Mol Cell Proteomics (2015) 14: 1569-83

Tyrosine phosphorylation of Nedd4-1 activates its ubiquitin ligase activity.
Persaud A, Alberts P, Mari S, Tong J, Murchie R, Maspero E, Safi F, Moran MF, Polo S, ROTIN D.
Science Signal. (2014) Oct; 7: ra95

Protein tyrosine phosphatase σ targets apical junction complex proteins in the intestine and regulates epithelial permeability
Murchie R, Guo CH, Persaud A, Muise A, ROTIN D
Proc. Natl. Acad. Sci. USA (2014) Jan 14; 111: 2: 693-8.

Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress.
Fang NN, Chan GT, Zhu M, Comyn SA, Persaud A, Deshaies RJ, ROTIN D, Gsponer J, Mayor T.
Nat. Cell Biol. (2014) 16: 1227-37.

Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function.
Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, ROTIN D.
EMBO J. (2011) Jul 15; 30: 16: 3259-73

Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease.
Kimura T, Kawabe H, Jiang C, Zhang W, Xiang YY, Lu C, Salter MW, Brose N, Lu WY, ROTIN
Proc. Natl. Acad. Sci. USA (2011) Feb 22; 108: 8: 3216-21

Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays.
Persaud A, Alberts P, Amsen EM, Xiong X, Wasmuth J, Saadon Z, Fladd C, Parkinson J, ROTIN D
Mol. Syst. Biol. (2009) Dec 1; 5: 333.

Physiological functions of the HECT family of ubiquitin ligases
ROTIN D and Kumar S.
Nat. Rev. Mol. Cell Biol. (2009) June; 10: 6: 398-409.

Use of kinase inhibitors to correct ΔF508-CFTR function
Trzcinska-Daneluti AM, Nguyen L, Jiang C, Fladd C, Uehling D, Prakesch M, Al-awar R, ROTIN D.
Mol. Cell. Proteomics (2012) Sep; 11: 9: 745-57

Protein Tyrosine Phosphatase sigma is associated with Ulcerative Colitis.
Muise A, Walters T, Wine E, Griffiths A, Duerr R, Turner D, Regueiro M, Ngan BY, Sherman P, Siverberg M, ROTIN D.
Curr. Biol. (2007): 17: 1212-18

Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma
Wallace MJ, Batt J, Fladd C, Henderson JT, Skarnes W, ROTIN D.
Nature Genet. (1999): 21: 334-8

WW domains of Nedd4 bind to the proline rich PY motifs in the epithelial Na channel deleted in Liddle’s syndrome.
Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, ROTIN D
EMBO J. (1996): 15: 2371-80