| Title: |
AuxB interacts directly with GpsB and PknB to coordinate cell envelope processes that contribute to intrinsic antibiotic resistance in Staphylococcus aureus |
| Authors: |
Sisley, Tyler A.; Park, Youngseon; Santiago, Ace George; Beroual, Wanassa; Sobolewski, Isabella A.; Lee, Wonsik; Paulo, Joao A.; Walker, Suzanne |
| Contributors: |
Laub, Michael T.; National Institutes of Health; National Science Foundation Graduate Research Fellowship Program; Howard Hughes Medical Institute; National Institute of General Medical Sciences |
| Source: |
mBio ; volume 16, issue 10 ; ISSN 2150-7511 |
| Publisher Information: |
American Society for Microbiology |
| Publication Year: |
2025 |
| Description: |
Staphylococcus aureus , a leading cause of serious infections, produces various factors important for intrinsic resistance to antibiotics. Understanding what intrinsic resistance factors do may enable strategies to potentiate existing antibiotics. The membrane protein AuxB is an intrinsic resistance factor that helps S. aureus withstand diverse compounds that target the cell envelope, but its cellular functions are unknown. We show here that AuxB is a four-pass transmembrane protein with an intracellular C-terminus that interacts directly with the cytosolic cell cycle regulator GpsB. We also show AuxB’s membrane domain forms a homodimer that exists in equilibrium with a heterodimer of AuxB and PknB, a eukaryotic-like serine/threonine kinase that has been implicated in cell envelope processes. Shifting the equilibrium to favor AuxB-bound PknB impairs growth on tunicamycin, a condition where PknB is essential, which suggests that AuxB binding antagonizes a PknB function. To link PknB’s domains to compound susceptibility phenotypes, we assessed the fitness of PknB variants under several conditions. We find that PknB’s extracellular and kinase domains are not functionally interdependent but instead play distinct roles in withstanding cell envelope stress. AuxB evidently antagonizes functions of PknB’s extracellular PASTA ( p enicillin-binding protein a nd S er/ T hr kinase- a ssociated) domain, the presence of which is beneficial under tunicamycin treatment regardless of whether the kinase domain is active. On compounds where the PASTA domain is deleterious, increasing the amount of AuxB-bound PknB can also ameliorate sensitivity. Collectively, our data suggest that AuxB, as a homodimer and through its interactions with GpsB and PknB, modulates cell envelope processes during cell growth and division. IMPORTANCE Staphylococcus aureus is a leading cause of fatal infections worldwide. It encodes diverse genes that contribute to the organism's high intrinsic resistance to antibiotics. Understanding the ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1128/mbio.01858-25 |
| Availability: |
https://doi.org/10.1128/mbio.01858-25; https://journals.asm.org/doi/pdf/10.1128/mbio.01858-25 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; https://journals.asm.org/non-commercial-tdm-license |
| Accession Number: |
edsbas.10F0C686 |
| Database: |
BASE |