Proteases in bacteriophage defense systems and their potential in bioengineering

Konstantinos Kalogeropoulos; Sam P.B. van Beljouw; Dani Feldmann; Daan F. van den Berg; Stan J.J. Brouns

doi:10.1016/j.tibs.2025.10.006

Proteases in bacteriophage defense systems and their potential in bioengineering

Konstantinos Kalogeropoulos^*, Sam P.B. van Beljouw, Dani Feldmann^*, Daan F. van den Berg, Stan J.J. Brouns

^*Corresponding author for this work

BN/Stan Brouns Lab

Research output: Contribution to journal › Review article › peer-review

Abstract

Novel phage defense systems featuring diverse enzymatic activities are continually being discovered. Among these, defense systems employing proteolytic enzymes have been identified, revealing a previously unrecognized enzymatic activity in phage defense. These protease-associated defense systems represent an untapped reservoir for new biotechnological tools and may serve as a springboard for the development of proteome editors. This review outlines recent advancements in the discovery and characterization of protease-containing defense systems, proposes methods for further exploration and investigation of protease activity, and considers the prospect of protease defense systems for modulating protein processing and cell fate.

Original language	English
Number of pages	16
Journal	Trends in Biochemical Sciences
DOIs	https://doi.org/10.1016/j.tibs.2025.10.006
Publication status	Accepted/In press - 2025

Keywords

CRISPR–Cas
phage defense
protease effectors
protease-associated defense systems (PADS)
protein engineering
proteome editing

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10.1016/j.tibs.2025.10.006

s12276-025-01585-zFinal published version, 2.62 MBLicence: CC BY-NC

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title = "Proteases in bacteriophage defense systems and their potential in bioengineering",

abstract = "Novel phage defense systems featuring diverse enzymatic activities are continually being discovered. Among these, defense systems employing proteolytic enzymes have been identified, revealing a previously unrecognized enzymatic activity in phage defense. These protease-associated defense systems represent an untapped reservoir for new biotechnological tools and may serve as a springboard for the development of proteome editors. This review outlines recent advancements in the discovery and characterization of protease-containing defense systems, proposes methods for further exploration and investigation of protease activity, and considers the prospect of protease defense systems for modulating protein processing and cell fate.",

keywords = "CRISPR–Cas, phage defense, protease effectors, protease-associated defense systems (PADS), protein engineering, proteome editing",

author = "Konstantinos Kalogeropoulos and {van Beljouw}, {Sam P.B.} and Dani Feldmann and {van den Berg}, {Daan F.} and Brouns, {Stan J.J.}",

year = "2025",

doi = "10.1016/j.tibs.2025.10.006",

language = "English",

journal = "Trends in Biochemical Sciences",

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TY - JOUR

T1 - Proteases in bacteriophage defense systems and their potential in bioengineering

AU - Kalogeropoulos, Konstantinos

AU - van Beljouw, Sam P.B.

AU - Feldmann, Dani

AU - van den Berg, Daan F.

AU - Brouns, Stan J.J.

PY - 2025

Y1 - 2025

N2 - Novel phage defense systems featuring diverse enzymatic activities are continually being discovered. Among these, defense systems employing proteolytic enzymes have been identified, revealing a previously unrecognized enzymatic activity in phage defense. These protease-associated defense systems represent an untapped reservoir for new biotechnological tools and may serve as a springboard for the development of proteome editors. This review outlines recent advancements in the discovery and characterization of protease-containing defense systems, proposes methods for further exploration and investigation of protease activity, and considers the prospect of protease defense systems for modulating protein processing and cell fate.

AB - Novel phage defense systems featuring diverse enzymatic activities are continually being discovered. Among these, defense systems employing proteolytic enzymes have been identified, revealing a previously unrecognized enzymatic activity in phage defense. These protease-associated defense systems represent an untapped reservoir for new biotechnological tools and may serve as a springboard for the development of proteome editors. This review outlines recent advancements in the discovery and characterization of protease-containing defense systems, proposes methods for further exploration and investigation of protease activity, and considers the prospect of protease defense systems for modulating protein processing and cell fate.

KW - CRISPR–Cas

KW - phage defense

KW - protease effectors

KW - protease-associated defense systems (PADS)

KW - protein engineering

KW - proteome editing

UR - http://www.scopus.com/inward/record.url?scp=105021661204&partnerID=8YFLogxK

U2 - 10.1016/j.tibs.2025.10.006

DO - 10.1016/j.tibs.2025.10.006

M3 - Review article

AN - SCOPUS:105021661204

SN - 0968-0004

JO - Trends in Biochemical Sciences

JF - Trends in Biochemical Sciences

ER -

Proteases in bacteriophage defense systems and their potential in bioengineering

Abstract

Keywords

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