Yifat Merbl received her PhD in Systems Biology from Harvard Medical School, after earning her BSc in Life Science and Computer Science, Bar-Ilan University, and her MSc in Immunology, Weizmann Institute of Science. She returned to the Weizmann Institute in 2014 to establish her independent research group. The Merbl lab has pioneered several platform technologies for profiling post-translational modifications and proteasomal degradation across biological systems and human disease. Most recently, they discovered a previously unknown cell-autonomous defense mechanism in which proteasomal degradation of cellular proteins generates peptides with antibacterial activity. Her team further uncovered how the proteasome alters its activity in response to bacterial infection, enabling the generation of these defense peptides. This discovery revealed an unexpected role for the proteasome in innate immunity and may provide the foundation for the development of a new class of antimicrobial agents. In recognition of this discovery and its scientific impact, Prof. Merbl was selected for Nature’s 10, the journal’s annual list of ten people who helped shape science in 2025.

Yifat is the recipient of numerous prestigious awards and competitive research grants, including the AACR Trailblazer Award, the CRI Lloyd J. Old STAR Award, the Rappaport Prize for Excellence in Biomedical Research, and both ERC Starting and Consolidator Grants. 

Orchid number: https://orcid.org/0000-0002-3465-2221
LinkedIn: https://www.linkedin.com/in/yifat-merbl-0b989838/
Website: https://www.weizmann.ac.il/immunology/merbl/ 

Compelling evidence suggests that many small-molecule drugs induce the degradation of target proteins both through known as well as unknown mechanisms of action, providing therapeutic opportunities but also creating potential safety liabilities. The central premise of Yifat’s work at AITHYRA is that drugs do not simply eliminate individual proteins but fundamentally reprogram proteasomal activity, generating distinct and context-dependent degradation landscapes that shape therapeutic efficacy, resistance, and immune engagement. The team proposes that these degradation landscapes encode actionable information that can be systematically measured and leveraged to predict drug performance across cancer contexts. This project builds upon unique conceptual and technical advances developed in Yifat’s lab. While the proteasome has traditionally been viewed as a terminal degradation machine, the Merbl lab has demonstrated that proteasome-generated peptides are biologically active regulators of immunity and cellular state. A proprietary approach - Mass Spectrometry Analysis of Proteasome-cleaved Peptides (MAPP) - enabled direct, in situ profiling of proteasomal degradation products in cells and tissues and the discovery of proteasome-derived defense peptides (PDDPs), revealing that proteasomal degradation products can function as biologically active immune regulators. 

Leveraging MAPP, Yifat’s research project at AITHYRA will ask a deceptively simple but unaddressed question: How, and how often, do anti-cancer drugs change the landscape of proteolytic peptides generated by the proteasome?

The team hypothesizes that drugs - across mechanisms of action - induce distinct, reproducible, and biologically meaningful remodeling of the proteasomal peptide landscape, and that these "degradomic signatures" can be learned and predicted to derive actionable information about efficacy, resistance, and immune engagement of small molecule drugs that is invisible to transcriptomic or abundance-based readouts.

Publication Highlights

Cell-autonomous innate immunity by proteasome-derived defence peptides. Goldberg, K, Lobov, A, Antonello, P, Shmueli, MD, Yakir, I, Weizman, T, Ulman, A, Sheban, D, Laser, E, Kramer, MP, Shteinvil, R, Chen, G, Ibraheem, A, Sysoeva, V, Fishbain-Yoskovitz, V, Mohapatra, G, Abramov, A, Shimshi, S, Ogneva, K, Nandy, M, Amidror, S, Bootz-Maoz, H, Kuo, SH, Dezorella, N, Kacen, A, Javitt, A, Lau, GW, Yissachar, N, Hayouka, Z, Merbl, Y. 2025. Nature 639, 1032–1041. doi: 10.1038/s41586-025-08615-w. 

The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC. Javitt, A, Shmueli, MD, Kramer, MP, Kolodziejczyk, AA, Cohen, IJ, Radomir, L, Sheban, D, Kamer, I, Litchfield, K, Bab-Dinitz, E, Zadok, O, Neiens, V, Ulman, A, Wolf-Levy, H, Eisenberg-Lerner, A, Kacen, A, Alon, M, Rêgo, AT, Stacher-Priehse, E, Lindner, M, Koch, I, Bar, J, Swanton, C, Samuels, Y, Levin, Y, da Fonseca, PCA, Elinav, E, Friedman, N, Meiners, S, Merbl, Y. 2023. Nature Cancer 4, 629–647. doi: 10.1038/s43018-023-00557-4. 

Post-translational modifications reshape the antigenic landscape of the MHC I immunopeptidome in tumors. Kacen A, Javitt A, Kramer MP, Morgenstern D, Tsaban T, Shmueli MD, Teo GC, da Veiga Leprevost F, Barnea E, Yu F, Admon A, Eisenbach L, Samuels Y, Schueler-Furman O, Levin Y, Nesvizhskii AI, Merbl Y. Nat Biotechnol. 2023 Feb;41(2):239-251. doi: 10.1038/s41587-022-01464-2.