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Ariel Stanhill, Associate Professor

Ariel Stanhill
Contact Info

Ariel Stanhill Department of Natural Sciences 1 University Road P.O.B. 808 Ra’anana 4353701, Israel
Office:972-9-7782166 Email:stanhill@openu.ac.il

Additional Information

My CRIS profile

Areas of Interest
  • Protein quality control
  • Mechanistic aspects of protein translocation and degradation
  • Development of biophysical assays for kinetic assessment of protein folding status and degradation

I am an Associate Professor of Biology in the Department of Natural and Life Sciences at the Open University of Israel. I study the process of protein quality control in the cell during normal and stress conditions.

In order to function properly, proteins are required to fold into a specific 3D structure that is obtained based on their amino-acid composition and greatly influenced by its biophysical surrounding. As such, changes in the cell (temp., redox state, availability of interacting partners and post-translational modifications) balance the efficiency of correct protein folding. Misfolded and mislocalized proteins are considered toxic to the cell as they can promiscuously interact non-specifically with cellular proteins. Surveillance mechanisms that constantly monitor the folding status of the proteome are vital for maintaining proper cellular function and are seldom impaired in pathological conditions. Recognized misfolded proteins are either salvaged by refolding or subjected to terminal proteolysis in order to maintain proteostasis and eliminate cellular proteotoxicity. The 26S proteasome is one of the major components in the cell that regulates protein catabolism and as such in subject to versatile regulation and modulations.

My research focuses on two aspects of the proteasome; proteasomal degradation of mislocalized proteins and proteasome adaptors.
The first subject deals with the degradation of proteins that have not successfully entered the Endoplasmic Reticulum. This occurs either naturally in cases of polypeptides bearing weak signal-peptides or in cases of signal-peptide bearing mutations that seldom manifest in pathophysiological conditions. The mislocalized proteins are degraded by the ubiquitin-proteasome system (UPS) in a process termed pre-emptive quality control (pQC). Yet, various components and mechanistic aspects of the pQC are still open questions that we address in our research.
The second subject deals with proteins that interact with the proteasome during specific stress conditions (adaptors such as Zfand2a:AIRAP) or in cases of protein complexes that exchange the 26S proteasome cap (as in the case of the PA28 complex). Topics such as how is the proteasome activity modulated by these changes and what are the cellular consequences of these adaptations, are questions being addressed in our research.
Our  research makes use of biochemical, molecular biology and genetic methodologies , both in recombinant protein assays as well as in-vivo mammalian tissue culture and mouse models.

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1998 - 2003
Ph.D. Biochemistry, The Hebrew University of Jerusalem, Israel
1996 - 1998
M.Sc. Biotechnology, The Hebrew University of Jerusalem, Israel
 (magna cum laude)
1993 - 1993
B.Sc. Biology, The Hebrew University of Jerusalem, Israel
2018 - current
Assistant Professor, Department of Natural and Life Sciences, The Open University, Israel
2016 - 2018
Visiting Scientist at Sheba Research Institute, Tel-HaShomer
2007 - 2015
Assistant Professor, Department of Biochemistry, Technion-Israel Institute of Technology, Haifa, Israel
2003 - 2007
Post-doctoral fellow, laboratory of Prof. David Ron, Department of Molecular Pathogenesis, Skirball Institute of Bimolecular Medicine, NYU Grossman School of Medicine

2015 - 2018     CSO at Tikcro Technologies (http://www.tikcro.com)
                          A Biotech company specializing in immune therapy antibodies

2020 - 2025
Israel Science Foundation (ISF)
“Ubiquitination of mislocalized proteins by RNF149 as a regulatory step in ER membrane translocation”
A. Stanhill, Principal Investigator
2019 - 2020
Israel cancer Association 
“Evaluating the cellular and pathological roles of RNF149in MPN formation”
2015 - 2018
Israel Science Foundation (ISF)
“Translocation into the endoplasmic reticulum is mediated by a novel P97 quality control complex”
A. Stanhill, Principal Investigator
2010 - 2011
Johns Hopkins University-Technion research grant 
“Translational regulation by means of leaky scanning”
A. Stanhill, Principal Investigator
2009 - 2013
Israel Science Foundation (ISF)
“Mechanisms of cellular response to proteasome inactivation”
A. Stanhill, Principal Investigator
2009 - 2011
Rappaport Family Institute for research in the Biomedical Sciences
“Adapting proteasomes to proteotoxicity by P97”
A. Stanhill, Principal Investigator
2009 - 2010
German Israeli Foundation (GIF)
“Transcriptional regulation of proteasome production in metazoa”
A. Stanhill, Principal Investigator
2009
Israel Science Foundation (ISF) Equipment Grant for new faculty members
A. Stanhill, Principal Investigator
2008 - 2011
Marie Curie International Reintegration grant (ERC-IRG)
“Proteasome adaptors”
A. Stanhill, Principal Investigator

2002           Abisch-Frenkel foundation fellowship for young investigators
2001           Hebrew university Rector Ph.D. fellowship
2001           Noach Lichtenstein Biological Chemistry Award
2000           Wolf foundation scholarship for Ph.D. students
1999           Deans prize for excellence in research

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1. Rahigi, S., I. Braunstein, M. Edri, N. Ternette, B. Kessler, A. Stanhill* and S. Wakatsuki. Architecture of the tandem UIMs determines selectivity of AIRAPL toward Lys48-linked ubiquitin chains. Structure 2016 24(3):412-22.).
* Corresponding author

2. Braunstein, I., Tzach, L. and A. Stanhill. Processing of poly-ubiquitinated pre-  emptive quality control substrates by an Airapl-p97 complex. Molecular Biology of the Cell 2015 26(21):3719-27.

3. Piterman, R., I. Braunstein, E. Isakov, T. Ziv, A. Navon, Cohen, S. and A. Stanhill. VWA domain of S5a restricts the ability to bind ubiquitin and Ubl to the 26S proteasome. Molecular Biology of the Cell 2014 25;(25):3988-98.

4. Tzach, L., I. Braunstein, and A. Stanhill. Stress induced start codon fidelity regulates arsenite inducible regulatory particle associated protein (AIRAP) translation. The Journal of biological chemistry 2014 ;289(30):20706-20716.

5. Berko, D., O. Herkon, I. Braunstein, Y. David, E. Isakov, T. Ziv, A. Admon, A. Navon and A. Stanhill  "Inherent asymmetry in the 26S proteasome is defined by the ubiquitin receptor Rpn13. The Journal of biological chemistry 2014; 289(9):5609-18.                  

6. Glinka, T., Y. Alter, I. Braunstein, L. Tzach, C. W. Sheng, S. Geifman, M. Edelmann, B. Kessler and A. Stanhill.  Signal-peptide mediated translocation is regulated by a P97-AIRAPL complex. Biochemical Journal, 2014; 457(2):253-61.  

7. Isakov, E., and A. Stanhill. Stalled proteasomes are directly relieved by P97 recruitment" The Journal of biological chemistry. 2011;286:30274-30283.

8. Wiseman, R. L., K. T. Chin, C. M. Haynes, A. Stanhill, C. F. Xu, A. Roguev, N. J. Krogan, T. A. Neubert, and D. Ron. Thioredoxin-related Protein 32 is an arsenite-regulated Thiol Reductase of the proteasome 19S particle. The Journal of biological chemistry. 2009;284:15233-15245.

9. Yun, C.*, A. Stanhill*, Y. Yang, Y. Zhang, C. M. Haynes, C. F. Xu, T. A. Neubert, A. Mor, M. R. Philips, and D. Ron. "Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 2008; 105:7094-7099.
*Equal contribution

10. Stanhill, A., V. Levin, A. Hendel, I. Shachar, D. Kazanov, N. Arber, N. Kaminski, and D. Engelberg. Ha-ras(val12) induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-ras(val12)-transformed cells. Oncogene 2006;25:1485-1495. 

11. Stanhill, A., C. M. Haynes, Y. Zhang, G. Min, M. C. Steele, J. Kalinina, E. Martinez, C. M. Pickart, X. P. Kong, and D. Ron. An arsenite-inducible 19S regulatory particle-associated protein adapts proteasomes to proteotoxicity. Molecular cell 2006;23:875-885.

12. Grably, M. R., A. Stanhill, O. Tell, and D. Engelberg. HSF and Msn2/4p can exclusively or cooperatively activate the yeast HSP104 gene. Molecular microbiology 2002;44:21-35.      

13. Stanhill, A., N. Schick, and D. Engelberg. The yeast ras/cyclic AMP pathway induces invasive growth by suppressing the cellular stress response. Molecular and cellular biology 1999; 19:7529-7538.     

14. Broder, Y. C., A. Stanhill, N. Zakai, A. Friedler, C. Gilon, and A. Loyter.   Translocation of NLS-BSA conjugates into nuclei of permeabilized mammalian cells can be supported by protoplast extract. An experimental system for studying plant cytosolic factors involved in nuclear import. FEBS letters 1997; 412:535-539.

Ciechanover, A., and A. Stanhill. The complexity of recognition of ubiquitinated substrates by the 26S proteasome. Biochimica et Biophysica Acta-Molecular Cell Research 2014;1843(1):86-96.       

Antibodies specific to CTLA-4 and uses thereof
International Publication Number WO 2020/058762 A1
Application Number PCT/IB2019/001038