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Stress testing reveals selective vulnerabilities in protein homeostasis
Berent Aldikacti1, Hidayet Putun1, Vishal Sarsani2
1Molecular and Cellular Biology Program, University of Massachusetts Amherst, Amherst, MA, USA; Biochemistry and Molecular Biology Department, University of Massachusetts Amherst, Amherst, MA, USA.
Cell Reports
|January 23, 2026
Summary
This study reveals hidden genetic vulnerabilities in bacterial protein quality control (PQC) systems. By analyzing gene fitness during proteotoxic stress, researchers uncovered stress-specific weaknesses in cellular resilience.
Area of Science:
- Cellular Biology
- Genetics
- Biochemistry
Background:
- Protein quality control (PQC) systems maintain cellular health under proteotoxic stress.
- Functional redundancies within PQC obscure the roles of individual genes.
- Understanding PQC vulnerabilities is crucial for cellular resilience.
Purpose of the Study:
- To identify hidden determinants of stress response in bacterial protein homeostasis.
- To uncover stress-specific vulnerabilities in PQC by profiling gene fitness.
- To reveal how major PQC players mask transcriptomic-fitness correlations.
Main Methods:
- Utilized transposon sequencing (Tn-seq) in bacterial strains lacking key chaperones and proteases.
- Profiled gene fitness under various proteotoxic stress conditions.
- Analyzed correlations between transcriptomic responses and gene fitness.
Main Results:
- Uncovered stress-specific vulnerabilities in PQC systems.
- Demonstrated that major PQC players mask gene fitness-transcriptomic correlations.
- Identified a heat-specific synthetic lethality involving ClpB, DNA polymerase 1, RecA aggregation, and heat shock regulon induction.
Conclusions:
- PQC vulnerabilities are specific to genetic and environmental contexts.
- The study presents a framework using gene fitness scores to reveal critical fragilities in stress responses.
- This approach is adaptable to various biological systems for understanding cellular resilience.
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