Prof. Shoshana Bar-Nun
Ph.D.: Hebrew University of Jerusalem, 1976
Phone: (Office): +972-3-6408984
(Lab): +972-3-6406695
(Home): +972-3-6094174
Fax (Office): +972-3-6406834
E-mail: shoshbn@tauex.tau.ac.il
Room#: Room 613 (office); room 611 (lab)
Member's portrait


Research Interests

Protein quality control mechanisms are the central focus of our research. These mechanisms play a key role in maintaining proteostasis and alleviate proteotoxic stresses. In the secretory pathway, nascent proteins are translocated across the endoplasmic reticulum (ER) membrane. Within the ER, N-glycans are attached, disulfide bonds are formed and proteins acquire secondary and tertiary structure and assemble into oligomeric complexes. Quality control mechanisms monitor folding and assembly, and only proteins that acquire native conformation exit the ER via vesicles and are transported to their final destinations along the secretory pathway.

Aberrant proteins are retained in the ER, dislocated back to the cytosol and eliminated by the ubiquitin-proteasome system. This  pathway is known as ER-associated protein degradation (ERAD) (Bar-Nun, 2005). Impaired quality control mechanisms underlie the molecular basis of diverse human diseases, including amyloidosis and neurodegenerative disorders such as Alzheimer's, Parkinsons's, Huntington's and polyglutamine and prion diseases. These disorders are in fact 'conformational diseases' caused by protein misfolding and aggregation.

Our research is aimed to understand the molecular mechanisms that underlie age-related neurodegeneration in general and aggregation of polyglutamine proteins in Huntington's disease in particular. Relying on the high degree of conservation of the quality control mechanisms and ERAD from yeast to man, our work utilizes molecular cell biology and biochemical techniques, both in cultured mammalian cells and in yeast. The power of yeast genetics and the simplicity of our assays allow identification of age-related pro- or anti-aggregation genes and conditions and the discovery of anti-aggregation drugs. These tools also allow us to study cis-acting signals that confer ER retention and ERAD onto otherwise stable and secreted proteins, as well as cellular trans-acting factors that target these proteins to degradation by the ubiquitin-proteasome system. As a model for cis-acting signals, we investigate elements derived from the immunoglobulin (Ig) molecule  that include CH1, the first constant region in Ig heavy chains, and mstp, the conserved glycosylated C-terminus of the ms heavy chain of secretory IgM. The cellular ERAD components that we focus on, addressing their role in ERAD and their regulation mode, include the AAA-ATPase p97/Cdc48 and the proteasome subunits.

Research Topics

 ·         Yeast as a model system for neurodegenerative disorders

 ·         The p97/Cdc48 AAA-ATPase and its Role in ERAD

 ·          ERAD signals


Selected Publications
  1. Bosis E, Salomon D, Ohayon O, Sivan G, Bar-Nun S, Rabinovich E. 2009. Ssz1 restores ERAD in cells expressing defective Cdc48-Ufd1-Npl4 complex by upregulating Cdc48. Genetics, in press
  2. Bosis E, Nachliel E, Cohen T, Takeda Y, Ito Y, Bar-Nun S, Gutman M. 2008. Endoplasmic reticulum glucosidase II is inhibited by its end products. Biochemistry. 47(41): 10970-80.
  3. Nadel G, Mayrose M, Burdelova O, Bar-Nun S. Competition for ERAD substrate between secretion and dislocation. Traffic, submitted
  4. Shapira I, Nimrod G, Ben-Tal N, Bar-Nun S. Characterization of a degron acting in the endoplasmic reticulum-associated degradation. In preparation
  5. Elkabetz Y, Ofir A, Argon Y, Bar-Nun S. 2008. Alternative pathways of disulfide bond  formation yield secretion-competent, stable and functional immunoglobulins. Mol. Immunol. 46(1): 97-105.
  6. Lipson C, Alalouf G, Bajorek M, Rabinovich E, Atir-Lande A, Glickman M, Bar-Nun S. 2008. A proteasomal ATPase Contributes to Dislocation of ERAD Substrates. J Biol Chem. 283(11): 7166-75.
  7. Shapira I, Charuvi D, Elkabetz Y, Hirschberg K, Bar-Nun S. 2007. Distinguishing between retention signals and degrons acting in ERAD. J Cell Sci. 120(24): 4377-87.
  8. Rabinovich E, Bajorek M, Glickman M, Bar-Nun, S. 2006. Proteasome channel opening as a rate limiting step in the ubiquitin-proteasome system. Israel Journal of Chemistry 46(2): 219-224.
  9. Bar-Nun S. 2005. The role of p97/Cdc48p in endoplasmic reticulum-associated degradation: from the immune system to yeast. In: Current Topics in Microbiology and Immunology: Dislocation and Degradation of Proteins from the Endoplasmic Reticulum; 300, pp. 95-125, Wiertz, Emmanuel J.H.J.; Kikkert, Marjolein (Eds.).
  10. Elkabetz Y, Argon Y, Bar-Nun S. 2005. Cysteines in CH1 underlie retention of unassembled Ig heavy chains. J Biol Chem. 280(15):. 14402-14412.
  11. Elkabetz Y, Shapira I, Rabinovich E, Bar-Nun S. 2004. Distinct steps in dislocation of luminal endoplasmic reticulum-associated degradation substrates: roles of endoplamic reticulum-bound p97/Cdc48p and proteasome. J Biol Chem. 279(6): 3980-9.
  12. Elkabetz Y, Kerem A, Tencer L, Winitz D, Kopito RR, Bar-Nun S. 2003. Immunoglobulin Light Chains Dictate Vesicular Transport-dependent and -independent Routes for IgM Degradation by the Ubiquitin-Proteasome Pathway. J Biol Chem 278(21): 18922-18929.
  13. *Rabinovich E, Kerem A, Frohlich KU, Diamant N, Bar-Nun S. 2002. AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 22(2): 626-34.
  14. Winitz D, Shachar I, Elkabetz Y, Amitay R, Samuelov M, Bar-Nun S. 1996. Degradation of distinct assembly forms of immunoglobulin M occurs in multiple sites in permeabilized B cells. J Biol Chem 271(44): 27645-51.
  15. Shachar I, Rabinovich E, Kerem A, Bar-Nun S. 1994. Thiol-reducing agents and calcium perturbants alter intracellular sorting of immunoglobulin M. J Biol Chem 269(44): 27344-50.
  16. Rabinovich E, Bar-Nun S, Amitay R, Shachar I, Gur B, Taya M, Haimovich J. 1993. Different assembly species of IgM are directed to distinct degradation sites along the secretory pathway. J Biol Chem 268(32): 24145-8.
  17. Kerem A, Kronman C, Bar-Nun S, Shafferman A, Velan B. 1993. Interrelations between assembly and secretion of recombinant human acetylcholinesterase. J Biol Chem 268(1): 180-4.
  18. Shachar I, Amitay R, Rabinovich E, Haimovich J, Bar-Nun S. 1992. Polymerization of secretory IgM in B lymphocytes is prevented by a prior targeting to a degradation pathway. J Biol Chem  267(34): 24241-7.
  19. Amitay R, Shachar I, Rabinovich E, Haimovich J, Bar-Nun S. 1992. Degradation of secretory immunoglobulin M in B lymphocytes occurs in a postendoplasmic reticulum compartment and is mediated by a cysteine protease. J Biol Chem 267(29): 20694-700.
  20. Amitay R, Bar-Nun S, Haimovich J, Rabinovich E, Shachar I. 1991. Post-translational regulation of IgM expression in B lymphocytes. Selective nonlysosomal degradation of assembled secretory IgM is temperature-dependent and occurs prior to the trans-Golgi. J. Biol. Chem. 266(19):12568-73.

     
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