Prof. Itay Koren
Protein degradation · Ubiquitin-proteasome system · Protein quality control · Degrons · E3 ligases · Ubiquitin · Proteasome · Proteostasis · Human disease
CV
Research
Decoding the language of protein degradation
Proteins are the building blocks of life, carrying out nearly every molecular function in the cell, from signal transduction to structural organization. Equally important is their regulated removal: cells must not only produce proteins, but also recognize when they are damaged, mislocalized, or no longer needed and eliminate them. Protein degradation is therefore central to virtually every cellular process, playing a critical role in protein quality control and the maintenance of protein homeostasis (proteostasis). Disruption of these processes contributes to a wide range of human diseases, including cancer, inflammation, and neurodegeneration.
The Koren Lab investigates the molecular mechanisms that control protein turnover in cells. We study how cells identify proteins for degradation, how degradation machineries recognize their targets, and how these pathways determine protein fate. At the center of our research is the ubiquitin-proteasome system (UPS), the major pathway responsible for selective protein degradation in human cells. We ask fundamental questions: What marks a protein for destruction? How are degradation signals (degrons) recognized? What roles do ubiquitin, E3 ubiquitin ligases, and the proteasome play in determining protein fate? And how do cells adapt their degradation machinery to changing conditions?
To address these questions, we develop and apply large-scale genomics, quantitative proteomics, biochemistry, cell biology, and computational approaches to systematically map protein degradation pathways. Our work has revealed mechanisms of ubiquitin-independent proteasomal degradation, an inter-organelle quality-control pathway linking mitochondria and peroxisomes, and degradation mechanisms with implications for human disease and cancer.
By uncovering how degradation pathways recognize and respond to different protein states, we seek to establish general principles of protein turnover, protein quality control, and proteostasis, and understand how their dysregulation contributes to disease.
Courses
- 80-242 — Molecular Biology and Genetic Engineering A (Pre-Medical Program).
- 80-377 — Molecular Biology and Genetic Engineering B.
- 80-308 — The Cellular Proteome: Protein Degradation Mechanisms and Quality Control Pathways
Publications
Selected Publications
1. Timms, RT., Zhang, Z., Rhee DY., Harper JW., Koren, I.#, Elledge, SJ.# (2019) A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science 365, eaaw4912.
Identifies a glycine-specific N-degron pathway mediated by the E3 ligase complexes Cul2–ZYG11B and Cul2–ZER1, revealing how cells recognize and eliminate proteins that fail to undergo N-myristoylation.
2. Timms, RT., Koren, I. (2020) Tying up loose ends: the N-degron and C-degron pathways of protein degradation. Biochem Soc Trans 48 (4): 1557–1567.
Reviews the mechanisms by which N-terminal and C-terminal degrons direct selective protein degradation, highlighting the expanding diversity of pathways that regulate protein stability in human cells.
3. Chen, X.*, Liao, S.*, Makaros, Y.*, Guo, Q., Zhu, Z., Krizelman, R., Dahan, K., Tu, X., Yao, X., Koren, I.#, Xu, C.# (2021) Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase. Nat Chem Biol 17(3):254-262
Reveals how FEM1-family E3 ligase substrate receptors recognize distinct arginine-ending C-degrons, explaining the molecular specificity of protein degradation and informing approaches to selectively regulate proteostasis.
4. Makaros, Y., Raiff, A., Timms, R.T., Wagh, A.R., Gueta, MI., Bekturova, A., Guez-Haddad, J., Brodsky, S., Opatowsky, Y., Glickman M.H., Elledge, S.J., Koren, I. (2023) Ubiquitin-independent proteasomal degradation driven by C-degron pathways. Mol Cell 83: 1921-1935.e7.
Demonstrates that C-degron pathways can direct proteins to the proteasome for degradation without requiring ubiquitination, revealing an alternative mechanism of selective protein turnover.
5. Zhao, S.*, Olmayev-Yaakobov*, D., Ru, W., Li, S., Chen, X., Zhang, J., Yao, X., Koren, I.#, Zhang, K.#, and Xu, C#. (2023). Molecular basis for C-degron recognition by CRL2APPBP2 ubiquitin ligase. Proc Natl Acad Sci U S A 120, e2308870120. 10.1073/pnas.2308870120.
Reveals the structural basis by which the CRL2–APPBP2 ubiquitin ligase recognizes specific C-terminal degrons, advancing our understanding of substrate selection and providing a foundation for structure-guided modulation of protein degradation.
6. Chen, X. *, Raiff, A. *, Li, S., Guo, Q., Zhang, J., Timms, R.T., Yao, X., Elledge, S.J., Koren, I. #, Zhang, K.#, Xu, C.# (2024) Molecular insights into the CRL2FEM1B ubiquitin ligase complex assembly and recognition of Ψ/Pro/C-degron. Nat Commun, 15(1):3558.
Uncovers how CRL2–FEM1B recognizes proline-ending C-degrons and how its assembly and NEDD8-dependent activation regulate protein ubiquitination and degradation.
7. Shimshon, A.*, Dahan, K.*, Israel-Gueta, M., Olmayev-Yaakobov, D., Timms, R.T., Bekturova, A., Makaros, Y., Elledge, S.J., Koren, I. (2024) Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability. JCB, Aug 5;223(8):e202311035. doi: 10.1083/jcb.202311035.
Demonstrates how the peptidases DPP8 and DPP9 cooperate with UBR E3 ligases to expose and recognize N-degrons, enabling the removal of mislocalized secretory proteins and maintaining cellular proteostasis
8. Zhang, Z., Mena, E., Timms, R.T.#, Koren, I.#, Elledge, S.J.# (2025) Degrons: defining the rules of protein degradation. Nat Rev Mol Cell Biol, 26(11):868-883. doi: 10.1038/s41580-025-00870-z.
Synthesizes advances in degron identification and recognition, explaining how degradation signals govern protein quality control, contribute to human disease, and enable emerging targeted protein degradation therapies.
9. Bekturova, A., Makaros, Y., Ben-David, S., Koren, I. (2025) Global Profiling of N-terminal Cysteine-Dependent Degradation Mechanisms. Proc Natl Acad Sci U S A. 122(33):e2501681122. doi: 10.1073/pnas.2501681122.
Systematically identifies proteins regulated by the N-terminal cysteine-dependent degradation pathway and reveals how this mechanism contributes to metabolic adaptation and cell survival under low-oxygen conditions.
10. Raiff, A.,*, Zhao, S.*, Bekturova1, A. Zenge, C., Mazor, S., Chen, X., Ru., W, Makaros, Y., Ast, T., Ordureau, A., Xu, C. #, Koren, I.# (2026) TOM20-Driven E3 Ligase Recruitment Regulates Mitochondrial Dynamics Through PLD6. Nat Chem Biol, 22(1):37-47. DOI: 10.1038/s41589-025-01894-4.
Identifies a mechanism by which the mitochondrial import receptor TOM20 recruits the E3 ligase complex CRL2–FEM1B to regulate PLD6 degradation, revealing how the ubiquitin-proteasome system controls mitochondrial dynamics and morphology.
11. Segev-Nakar, S., and Koren, I. (2026) A mitochondria-driven quality control mechanism for peroxisomal membrane proteins. Nat Commun. doi: 10.1038/s41467-026-74117-6.
Reveals an inter-organelle quality-control mechanism in which mitochondria recognize and eliminate mislocalized peroxisomal membrane proteins through the E3 ligases MUL1 and MARCH5, maintaining cellular proteostasis when peroxisomes are absent.
Media
Two ERC Proof of Concept Grants, Two Groundbreaking Projects | Bar-Ilan University, Facebook | Announcement highlighting two ERC Proof of Concept grants awarded to Bar-Ilan University researchers.
Last Updated Date : 13/10/2026
