Cell-autonomous innate immunity by proteasome-derived defence peptides

Karin Goldberg, Arseniy Lobov, Paola Antonello, Merav D. Shmueli, Idan Yakir, Tal Weizman, Adi Ulman, Daoud Sheban, Einav Laser, Matthias P. Kramer, Ronen Shteinvil, Guoyun Chen, Angham Ibraheem, Vera Sysoeva, Vered Fishbain-Yoskovitz, Gayatree Mohapatra, Anat Abramov, Sandy Shimshi, Kseniia Ogneva, Madhurima Nandy, Sivan Amidror, Hadar Bootz-Maoz, Shanny H. Kuo, Nili Dezorella, Assaf Kacen, Aaron Javitt, Gee W. Lau, Nissan Yissachar, Zvi Hayouka and Yifat Merbl ()
Additional contact information
Karin Goldberg: Weizmann Institute of Science
Arseniy Lobov: Weizmann Institute of Science
Paola Antonello: Weizmann Institute of Science
Merav D. Shmueli: Weizmann Institute of Science
Idan Yakir: The Hebrew University of Jerusalem
Tal Weizman: Weizmann Institute of Science
Adi Ulman: Weizmann Institute of Science
Daoud Sheban: Weizmann Institute of Science
Einav Laser: Weizmann Institute of Science
Matthias P. Kramer: Weizmann Institute of Science
Ronen Shteinvil: Weizmann Institute of Science
Guoyun Chen: Weizmann Institute of Science
Angham Ibraheem: Weizmann Institute of Science
Vera Sysoeva: Weizmann Institute of Science
Vered Fishbain-Yoskovitz: Weizmann Institute of Science
Gayatree Mohapatra: Weizmann Institute of Science
Anat Abramov: Weizmann Institute of Science
Sandy Shimshi: Weizmann Institute of Science
Kseniia Ogneva: Weizmann Institute of Science
Madhurima Nandy: Weizmann Institute of Science
Sivan Amidror: Bar-Ilan University
Hadar Bootz-Maoz: Bar-Ilan University
Shanny H. Kuo: University of Illinois
Nili Dezorella: Weizmann Institute of Science
Assaf Kacen: Weizmann Institute of Science
Aaron Javitt: Weizmann Institute of Science
Gee W. Lau: University of Illinois
Nissan Yissachar: Bar-Ilan University
Zvi Hayouka: The Hebrew University of Jerusalem
Yifat Merbl: Weizmann Institute of Science

Nature, 2025, vol. 639, issue 8056, 1032-1041

Abstract: Abstract For decades, antigen presentation on major histocompatibility complex class I for T cell-mediated immunity has been considered the primary function of proteasome-derived peptides1,2. However, whether the products of proteasomal degradation play additional parts in mounting immune responses remains unknown. Antimicrobial peptides serve as a first line of defence against invading pathogens before the adaptive immune system responds. Although the protective function of antimicrobial peptides across numerous tissues is well established, the cellular mechanisms underlying their generation are not fully understood. Here we uncover a role for proteasomes in the constitutive and bacterial-induced generation of defence peptides that impede bacterial growth both in vitro and in vivo by disrupting bacterial membranes. In silico prediction of proteome-wide proteasomal cleavage identified hundreds of thousands of potential proteasome-derived defence peptides with cationic properties that may be generated en route to degradation to act as a first line of defence. Furthermore, bacterial infection induces changes in proteasome composition and function, including PSME3 recruitment and increased tryptic-like cleavage, enhancing antimicrobial activity. Beyond providing mechanistic insights into the role of proteasomes in cell-autonomous innate immunity, our study suggests that proteasome-cleaved peptides may have previously overlooked functions downstream of degradation. From a translational standpoint, identifying proteasome-derived defence peptides could provide an untapped source of natural antibiotics for biotechnological applications and therapeutic interventions in infectious diseases and immunocompromised conditions.

Date: 2025
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DOI: 10.1038/s41586-025-08615-w

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