Prof. Shoshana Bar-Nun

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.

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 include:

• Yeast as a model system for neurodegenerative disorders
• The p97/Cdc48 AAA-ATPase and its role in ERAD
• ERAD signals

Please read a more detailed research description.

ATP Binding to p97/VCP D1 Domain Regulates Selective Recruitment of Adaptors to Its Proximal N-Domain. Chia WS, Chia DX, Rao F, Bar-Nun S, Geifman Shochat S. PLoS One. 2012;7(12):e50490. Pubmed Link

Aggregation of polyQ proteins is increased upon yeast aging and affected by Sir2 and Hsf1: novel quantitative biochemical and microscopic assays. Cohen A, Ross L, Nachman I, Bar-Nun S. PLoS One. 2012;7(9):e44785. Pubmed Link

Proteasomal AAA-ATPases: structure and function. Bar-Nun S, Glickman MH. Biochim Biophys Acta. 2012 Jan;1823(1):67-82. Review. Pubmed Link

Ssz1 restores endoplasmic reticulum-associated protein degradation in cells expressing defective cdc48-ufd1-npl4 complex by upregulating cdc48. Bosis E, Salomon D, Ohayon O, Sivan G, Bar-Nun S, Rabinovich E. Genetics. 2010 Mar;184(3):695-706. Pubmed Link

Endoplasmic reticulum glucosidase II is inhibited by its end products. Bosis E, Nachliel E, Cohen T, Takeda Y, Ito Y, Bar-Nun S, Gutman M. Biochemistry. 2008 Oct 14;47(41):10970-80. Pubmed Link

Alternative pathways of disulfide bond formation yield secretion-competent, stable and functional immunoglobulins. Elkabetz Y, Ofir A, Argon Y, Bar-Nun S. Mol Immunol. 2008 Nov;46(1):97-105. Pubmed Link

A proteasomal ATPase contributes to dislocation of endoplasmic reticulum-associated degradation (ERAD) substrates. Lipson C, Alalouf G, Bajorek M, Rabinovich E, Atir-Lande A, Glickman M, Bar-Nun S. J Biol Chem. 2008 Mar 14;283(11):7166-75. Pubmed Link

Distinguishing between retention signals and degrons acting in ERAD. Shapira I, Charuvi D, Elkabetz Y, Hirschberg K, Bar-Nun S. J Cell Sci. 2007 Dec 15;120(Pt 24):4377-87. Pubmed Link

The role of p97/Cdc48p in endoplasmic reticulum-associated degradation: from the immune system to yeast. Bar-Nun S. Curr Top Microbiol Immunol. 2005;300:95-125. Review. Pubmed Link

Cysteines in CH1 underlie retention of unassembled Ig heavy chains. Elkabetz Y, Argon Y, Bar-Nun S. J Biol Chem. 2005 Apr 15;280(15):14402-12. Pubmed Link

Distinct steps in dislocation of luminal endoplasmic reticulum-associated degradation substrates: roles of endoplamic reticulum-bound p97/Cdc48p and proteasome. Elkabetz Y, Shapira I, Rabinovich E, Bar-Nun S. J Biol Chem. 2004 Feb 6;279(6):3980-9. Pubmed Link

Immunoglobulin light chains dictate vesicular transport-dependent and -independent routes for IgM degradation by the ubiquitin-proteasome pathway. Elkabetz Y, Kerem A, Tencer L, Winitz D, Kopito RR, Bar-Nun S. J Biol Chem. 2003 May 23;278(21):18922-9. Pubmed Link

AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Rabinovich E, Kerem A, Fröhlich KU, Diamant N, Bar-Nun S. Mol Cell Biol. 2002 Jan;22(2):626-34. Pubmed Link

Degradation of distinct assembly forms of immunoglobulin M occurs in multiple sites in permeabilized B cells. Winitz D, Shachar I, Elkabetz Y, Amitay R, Samuelov M, Bar-Nun S. J Biol Chem. 1996 Nov 1;271(44):27645-51. Pubmed Link

Thiol-reducing agents and calcium perturbants alter intracellular sorting of immunoglobulin M. Shachar I, Rabinovich E, Kerem A, Bar-Nun S. J Biol Chem. 1994 Nov 4;269(44):27344-50. Pubmed Link

Different assembly species of IgM are directed to distinct degradation sites along the secretory pathway. Rabinovich E, Bar-Nun S, Amitay R, Shachar I, Gur B, Taya M, Haimovich J. J Biol Chem. 1993 Nov 15;268(32):24145-8. Pubmed Link

Interrelations between assembly and secretion of recombinant human acetylcholinesterase. Kerem A, Kronman C, Bar-Nun S, Shafferman A, Velan B. J Biol Chem. 1993 Jan 5;268(1):180-4. Pubmed Link

Polymerization of secretory IgM in B lymphocytes is prevented by a prior targeting to a degradation pathway. Shachar I, Amitay R, Rabinovich E, Haimovich J, Bar-Nun S. J Biol Chem. 1992 Dec 5;267(34):24241-7. Pubmed Link

Degradation of secretory immunoglobulin M in B lymphocytes occurs in a postendoplasmic reticulum compartment and is mediated by a cysteine protease. Amitay R, Shachar I, Rabinovich E, Haimovich J, Bar-Nun S. J Biol Chem. 1992 Oct 15;267(29):20694-700. Pubmed Link

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. Amitay R, Bar-Nun S, Haimovich J, Rabinovich E, Shachar I. J Biol Chem. 1991 Jul 5;266(19):12568-73. Pubmed Link