About BEB
CNC Research
BEB in the Media
Biology of Proteolysis
March 6 - 10
Coordinator: Paulo Pereira

Mayo Clinic College of Medicine, Rochester, MN. USA
Cell and Developmental Biology section, University of California, San Diego, CA, USA
Department of Physiology & Biophysics, University of Iowa, Iowa City, IA, USA
IBILI – Faculty of Medicine, University of Coimbra, Portugal
Web-page: www.ibili.uc.pt

Course Schedule
Monday 5th march
Hampton -  overview of Ub-dependent proteolysis (emphasis on proteasome)
Coffee break
Katzmann - overview of Ub-dependent proteolysis (emphasis on lysosome)
Piper - ubiquitin structure, linkages, implications
Tuesday 6th march
Katzmann - emphasis on ligases
Coffee break
Piper -  emphsis on deubiquitinating enzymes
journal club (from a selection of papers)
JC1 - students presenting: Eduardo Ferreira and Ana Cristovão
JC2 - Students presenting: Gisela Silva and  Ana Isabel Teles
Wednesday, 7th march
Hampton - protein quality control
Coffee break
Hampton - cholesterol sensing/metabolism
journal club (from a selection of papers)
JC3 - students presenting: Helena Domingues and Carina Santos 
JC4 - Students presenting: Joana Lourenço e Catarina Pimentel
Thursday, 8th march
Piper - ubiquitin recognition by adapters and ubiquitnation thereof
Coffee break
Katzmann - Autophagy
journal club (from a selection of papers)
JC5 - students presenting: Ligia Gomes and Mariana Bexiga
JC7 - Students presenting: Ricardo Marques and Ricardo Soares
Friday, 9th march
Katzmann - non-proteolytic roles for degradative machinery
Piper -  ubiquitin-like modifications
Seminário de 6a feira à tarde
"Regulation of Multivesicular Body cargo recognition and sorting"
David J Katzmann
Mayo Clinic College of Medicine, Rochester, MN. USA
Affiliation, Contacts and Selected Publications
David J Katzmann - Mayo Clinic College of Medicine, Rochester, MN. USA
Web: mayoresearch.mayo.edu/mayo/research/staff/katzmann_dj.cfm
Katzmann DJ , Sarkar S , Chu T , Audhya A , Emr SD . Multivesicular body sorting: ubiquitin ligase Rsp5 is required for the modification and sorting of carboxypeptidase S. Mol Biol Cell 2004 Feb; 15(2):468-80.
Odorizzi G , Katzmann DJ , Babst M , Audhya A , Emr SD . Bro1 is an endosome-associated protein that functions in the MVB pathway in Saccharomyces cerevisiae. J Cell Sci 2003 May 15; 116(Pt 10):1893-903.
Shih SC , Katzmann DJ , Schnell JD , Sutanto M , Emr SD , Hicke L . Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis. Nat Cell Biol 2002 May; 4(5):389-93.
Babst M , Katzmann DJ , Snyder WB , Wendland B , Emr SD . Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev Cell 2002 Aug; 3(2):283-9.
Randy Hampton - Cell and Developmental Biology section, University of California, San Diego, CA, USA
WEB: www-biology.ucsd.edu/faculty/hampton.html (Lab page: hamptonlab.ucsd.edu/)
Federovitch CM, Ron D, Hampton RY. The dynamic ER: experimental approaches and current questions.Curr Opin Cell Biol. 2005:17(4):409-14. Review.
Garza RM, Hampton RY. Cell biology: sterol sensor comes up for air. Nature. 2005 5;435(7038):37-8.
Bazirgan OA, Hampton RY. Cdc48-Ufd2-Rad23: the road less ubiquitinated? Nat Cell Biol. 2005 7(3):207-9.
Shearer AG, Hampton RY. Lipid-mediated, reversible misfolding of a sterol-sensing domain protein. EMBO J. 2005:12;24(1):149-59.
Robert C Piper - Department of Physiology & Biophysics, University of Iowa, Iowa City, IA, USA
Bilodeau PS, Urbanowski JL, Winistorfer SC, Piper RC. (2002) The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting. Nature Cell Biol 4 (7), 534-539
Bilodeau PS, Winistorfer SC, Kearney WR, Robertson AD, Piper RC. (2003) Vps27-Hse1 and ESCRT-I complexes cooperate to increase efficiency of sorting ubiquitinated proteins at the endosome. J Cell Biol 163 (2), 237-243
Scott PM, Bilodeau PS, Zhdankina O, Winistorfer SC, Hauglund MJ, Allaman MM, Kearney WR, Robertson AD, Boman AL, Piper RC. GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network. Nature Cell Biol 6 (3), 252-259
Richardson SC, Winistorfer SC, Poupon V, Luzio JP, Piper RC. (2004) Mammalian late vacuole protein sorting orthologues participate in early endosomal fusion and interact with the cytoskeleton. Mol Biol Cell 15 (3), 1197-1210
Marques C, Guo W, Pereira P, Taylor A, Petterson C, Evans P and Shang F. The triage of damaged proteins: Degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J. 2005 (in press)
Girão H, Pereira P, Taylor A and Shang F. Subcellular Redistribution of Components of the Ubiquitin-Proteasome Pathway during Lens Differentiation and Maturation.Invest Ophthalmol Vis Sci. 2005, 46:1386-92.
Fernandes R, Girão H and Pereira P. High glucose downregulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism. J Biol Chem. 2004, 279:27219-27224.
Girao H, Catarino S. and Pereira P. 7-Ketocholesterol modulates intercellular communication through gap-junction in bovine lens epithelial cells. Cell Communication and Signaling. 2004, 2:2.
Each group of two students should indicate a paper of their choice to be presented in journal club.
Papers in Blue are potential background reading and/ or primary papers that significantly contributed to the advance of knowledge in important areas.
Papers preceded by * often represent different and controversial views on the same subject and would benefit from being presented in the same session.
Students should inform the coordinators of the course of the papers that they have chosen for the journal clubs at least 2 days before the presentations.
Babst, M. A protein´s final ESCRT. Traffic 2005 6: 2-9
Katzmann, D. J., Odorizzi, G., Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 2002 3: 893-905

d´Azzo A, Bongiovanni A, Nastasi T. E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation.
Traffic. 2005 Jun;6(6):429-41.

Lufen Chang, Hideaki Kamata, Giovanni Solinas, Jun-Li Luo, Shin Maeda, K. Venuprasad, Yun-Cai Liu, and Michael Karin
The E3 Ubiquitin Ligase Itch Couples JNK Activation to TNFα-induced Cell Death by Inducing c-FLIPL Turnover
Cell 2006 124: 601-613

Qing Zhong, Wenhua Gao, Fenghe Du, and Xiaodong Wang
Mule/ARF-BP1, a BH3-Only E3 Ubiquitin Ligase, Catalyzes the Polyubiquitination of Mcl-1 and Regulates Apoptosis
Cell 2005 121: 1085-1095.

Philippe Soubeyran, Katarzyna Kowanetz, Iwona Szymkiewicz, Wallace Y. Langdon, Ivan Dikic Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors Nature  416, 183-187

Daniela Jozic, Nayra Cárdenes, Yonathan Lissanu Deribe, Gabriel Moncalián, Daniela Hoeller, Yvonne Groemping, Ivan Dikic, Katrin Rittinger, Jerónimo Bravo Cbl promotes clustering of endocytic adaptor proteins Nature Structural & Molecular Biology  12, 972-979

Daniela Tosoni, Claudia Puri, Stefano Confalonieri, Anna Elisabetta Salcini, Pietro De Camilli, Carlo Tacchetti, and Pier Paolo Di Fiore
TTP Specifically Regulates the Internalization of the Transferrin Receptor
Cell 2005 123: 875-888.

Ian J White, Lorna M Bailey, Minoo Razi Aghakhani, Stephen E Moss, Clare E Futter EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation the EMBO Journal  25, 1-12

Bache, K. G., Brech, A., Mehlum, A., Stenmark, H. Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes J Cell Biol. 162: 435-42

Bilodeau, P. S., Urbanowski, J. L., Winistorfer, S. C., Piper, R. C. The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting. Nature Cell Biology 4:534-9

Katzmann, D. J., Stefan, C. J., Babst, M., Emr, S. D. Vps27 recruits ESCRT machinery to endosomes during MVB sorting. J. Cell Biol. 162:413-23

Katzmann, D. J., Babst, M., Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106:145-55

Urbanowski, J. L., Piper, R. C. Ubiquitin Sorts Proteins into the Intralumenal Degradative Compartment of the Late-Endosome/Vacuole. Traffic 2:622-30

Reggiori, F., Pelham, H. R. Sorting of proteins into multivesicular bodies: ubiquitin-dependent and -independent targeting EMBO 20: 5176-86

Sato, T. K., Overduin, M., Emr, S. D. Location, location, location: membrane targeting directed by PX domains. Science 294:1881-5

Odorizzi, G., Katzmann, D. J., Babst, M., Audhya, A., Emr, S. D. Bro1 is an endosome-associated protein that functions in the MVB pathway in Saccharomyces cerevisiae. J Cell Science 116: 1893-903 (This one describes a cute genetic screen that was performed and implicated the class E vps mutants as defective for MVB sorting.)

Yule Liu, Michael Schiff, Kirk Czymmek, Zsolt Tallóczy, Beth Levine, and S.P. Dinesh-Kumar
Autophagy Regulates Programmed Cell Death during the Plant Innate Immune Response
Cell 2005 121: 567-577.

Yoshinobu Ichimura, Takayoshi Kirisako, Toshifumi Takao, Yoshinori Satomi, Yasutsugu Shimonishi, Naotada Ishihara, Noboru Mizushima, Isei Tanida, Eiki Kominami, Mariko ... A ubiquitin-like system mediates protein lipidation Nature  408, 488-492

Tor Erik Rusten, Karine Lindmo, Gábor Juhász, Miklós Sass, Per O. Seglen, Andreas Brech, and Harald Stenmark
Programmed Autophagy in the

Drosophila Fat Body Is Induced by Ecdysone through Regulation of the PI3K Pathway
Developmental Cell 2004 7: 179-192

Ryan C. Scott, Oren Schuldiner, and Thomas P. Neufeld
Role and Regulation of Starvation-Induced Autophagy in the

Drosophila Fat Body
Developmental Cell 2004 7: 167-178.

Sophie Pattingre, Amina Tassa, Xueping Qu, Rita Garuti, Xiao Huan Liang, Noboru Mizushima, Milton Packer, Michael D. Schneider, and Beth Levine
Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy
Cell 2005 122: 927-939.

Wilkinson KD.
The discovery of ubiquitin-dependent proteolysis.
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15280-2
*Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR.

Rapid degradation of a large fraction of newly synthesized proteins by proteasomes.
Nature. 2000 Apr 13;404(6779):770-4.

*Vabulas RM, Hartl FU.
Protein synthesis upon acute nutrient restriction relies on proteasome function.
Science. 2005 Dec 23;310(5756):1960-3

Quality control in the endoplasmic reticulum
Lars Ellgaard, Ari Helenius Nature Reviews Molecular Cell Biology  4, 181-191  (01 Mar 2003)

The unfolded protein response in nutrient sensing and differentiation
Randal J. Kaufman, Donalyn Scheuner, Martin Schröder, Xiaohua Shen, Kyungho Lee, Chuan Yin Liu, Stacey M. Arnold Nature Reviews Molecular Cell Biology  3, 411-421

Cox JS, Shamu CE, Walter P.
Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.
Cell. 1993 Jun 18;73(6):1197-206.

Cox JS, Walter P.
A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response.
Cell. 1996 Nov 1;87(3):391-404.

Harding HP, Zhang Y, Ron D.
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.
Nature. 1999 Jan 21;397(6716):271-4

Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL.
ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.
Mol Cell. 2000 Dec;6(6):1355-64


Joseph L. Goldstein, Russell A. DeBose-Boyd, and Michael S. Brown
Protein Sensors for Membrane Sterols
Cell 2006 124: 35-46

Axel Nohturfft, Daisuke Yabe, Joseph L. Goldstein, Michael S. Brown, and Peter J. Espenshade
Regulated Step in Cholesterol Feedback Localized to Budding of SCAP from ER Membranes
Cell 2000 102: 315-323.

Tong Yang, Peter J. Espenshade, Michael E. Wright, Daisuke Yabe, Yi Gong, Ruedi Aebersold, Joseph L. Goldstein, and Michael S. Brown
Crucial Step in Cholesterol Homeostasis: Sterols Promote Binding of SCAP to INSIG-1, a Membrane Protein that Facilitates Retention of SREBPs in ER
Cell 2002 110: 489-500.

Nohturfft A, Losick R.
Cell biology. Fats, flies, and palmitate.
Science. 2002 May 3;296(5569):857-8.

Dobrosotskaya IY, Seegmiller AC, Brown MS, Goldstein JL, Rawson RB.
Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila.
Science. 2002 May 3;296(5569):879-83.

Dobrosotskaya IY, Goldstein JL, Brown MS, Rawson RB.
Reconstitution of sterol-regulated endoplasmic reticulum-to-Golgi transport of SREBP-2 in insect cells by co-expression of mammalian SCAP and Insigs.
J Biol Chem. 2003 Sep 12;278(37):35837-43. Epub 2003 Jul 3.
PMID: 12842885 [PubMed - indexed for MEDLINE]

Song BL, Sever N, DeBose-Boyd RA.
Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase.
Mol Cell. 2005 Sep 16;19(6):829-40.

Song BL, Javitt NB, DeBose-Boyd RA.
Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol.
Cell Metab. 2005 Mar;1(3):179-89.

Stephen P. Baker and Patrick A. Grant
The Proteasome: Not Just Degrading Anymore
Cell 2005 123: 361-363

Flury I, Garza R, Shearer A, Rosen J, Cronin S, Hampton RY.
INSIG: a broadly conserved transmembrane chaperone for sterol-sensing domain proteins.
EMBO J. 2005 Nov 16;24(22):3917-26
Mark Hochstrasser
Lingering Mysteries of Ubiquitin-Chain Assembly
Cell 2006 124: 27-34

Hicke L, Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins.
Annu Rev Cell Dev Biol. 2003;19:141-72.

Michael Rape, Sashank K. Reddy, and Marc W. Kirschner
The Processivity of Multiubiquitination by the APC Determines the Order of Substrate Degradation
Cell 2006 124: 89-103.

Matthew D. Petroski and Raymond J. Deshaies
Mechanism of Lysine 48-Linked Ubiquitin-Chain Synthesis by the Cullin-RING Ubiquitin-Ligase Complex SCF-Cdc34
Cell 2005 123: 1107-1120.

Rosa Puertollano, Paul A. Randazzo, John F. Presley, Lisa M. Hartnell, and Juan S. Bonifacino
The GGAs Promote ARF-Dependent Recruitment of Clathrin to the TGN
Cell 2001 105: 93-102.

Patricia M. Scott, Patricia S. Bilodeau, Olga Zhdankina, Stanley C. Winistorfer, Melissa J. Hauglund, Margaret M. Allaman, William R. Kearney, Andrew D. Robertson, Annette GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network Nature Cell Biology  6, 252-259  (01 Mar 2004)

Doray B, Ghosh P, Griffith J, Geuze HJ, Kornfeld Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network.
Science. 2002 Sep 6;297(5587):1700-3


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