Connection between protein-tyrosine kinase inhibition and coping with oxidative stress in Bacillus subtilis
Artikel i vetenskaplig tidskrift, 2024

In bacteria, attenuation of protein-tyrosine phosphorylation occurs during oxidative stress. The main described mechanism behind this effect is the H2O2-triggered conversion of bacterial phospho-tyrosines to protein-bound 3,4-dihydroxyphenylalanine. This disrupts the bacterial tyrosine phosphorylation-based signaling network, which alters the bacterial polysaccharide biosynthesis. Herein, we report an alternative mechanism, in which oxidative stress leads to a direct inhibition of bacterial protein-tyrosine kinases (BY-kinases). We show that DefA, a minor peptide deformylase, inhibits the activity of BY-kinase PtkA when Bacillus subtilis is exposed to oxidative stress. High levels of PtkA activity are known to destabilize B. subtilis pellicle formation, which leads to higher sensitivity to oxidative stress. Interaction with DefA inhibits both PtkA autophosphorylation and phosphorylation of its substrate Ugd, which is involved in exopolysaccharide formation. Inactivation of defA drastically reduces the capacity of B. subtilis to cope with oxidative stress, but it does not affect the major oxidative stress regulons PerR, OhrR, and Spx, indicating that PtkA inhibition is the main pathway for DefA involvement in this stress response. Structural analysis identified DefA residues Asn95, Tyr150, and Glu152 as essential for interaction with PtkA. Inhibition of PtkA depends also on the presence of a C-terminal α-helix of DefA, which resembles PtkA-interacting motifs from known PtkA activators, TkmA, SalA, and MinD. Loss of either the key interacting residues or the inhibitory helix of DefA abolishes inhibition of PtkA in vitro and impairs postoxidative stress recovery in vivo, confirming the involvement of these structural features in the proposed mechanism.

bacterial protein-tyrosine kinases

oxidative stress

protein-tyrosine phosphorylation


Lei Shi

Chalmers, Life sciences, Systembiologi

Abderahmane Derouiche

King Abdullah University of Science and Technology (KAUST)

Chalmers, Life sciences, Systembiologi

Santosh Pandit

Chalmers, Life sciences, Systembiologi

Meshari Alazmi

University of Hail

King Abdullah University of Science and Technology (KAUST)

M. Ventroux

Université Paris-Saclay

Julie Bonne Køhler

Novo Nordisk Fonden

M. F. Noirot-Gros

Université Paris-Saclay

Xin Gao

King Abdullah University of Science and Technology (KAUST)

Ivan Mijakovic

Novo Nordisk Fonden

Chalmers, Life sciences, Systembiologi

Proceedings of the National Academy of Sciences of the United States of America

0027-8424 (ISSN) 1091-6490 (eISSN)

Vol. 121 25


Biokemi och molekylärbiologi






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