The phage shock protein A (PspA) maintains membrane potential and supports NADH dehydrogenase function in mycobacteria
- 1Rutgers University, Newark
Abstract
Maintenance of membrane integrity and proton motive force (PMF) is critical for bacterial survival. The phage shock protein (Psp) system, conserved across bacterial species, stabilizes the membrane, maintains PMF, and protects against envelope damage. However, how the conserved effector PspA contributes to PMF maintenance remains unclear. Here, using the mycobacterial Psp system as a genetically tractable model, we provide mechanistic insight into this process. We show that PspA and the accessory protein PspM jointly sustain membrane potential, with PspM required to maintain a ~70 kDa PspA isoform at the membrane during envelope stress. Loss of PspA increases susceptibility to thioridazine, which targets type II NADH dehydrogenase (NDH-2), and to Ro 48-8071, an inhibitor of menaquinone biosynthesis. Notably, hypersusceptibility to thioridazine is rescued by exogenous menaquinone. Consistent with these phenotypes, a pspA-deficient mutant exhibits impaired NADH dehydrogenase activity despite unchanged abundance of NDH-2 and menaquinone (MK-9). Together, these findings identify a functional link between PspA and NADH dehydrogenase-dependent respiration and suggest that PspA contributes to PMF maintenance by supporting respiratory electron transfer.
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BibTeX
@misc{datta2026phage,
title = {{The phage shock protein A (PspA) maintains membrane potential and supports NADH dehydrogenase function in mycobacteria}},
author = {P. Datta and R. Provvedi and C. D. Sohaskey and R. Ukey and J. Puffal and M. Prithviraj and A. Tellez and A. Saleh and R. Khan and R. Manganelli and Y. S. Morita and K. Y. Rhee and M. L. Gennaro},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.750162},
url = {https://www.biorxiv.org/content/10.64898/2026.09.09.750162v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - The phage shock protein A (PspA) maintains membrane potential and supports NADH dehydrogenase function in mycobacteria
AU - P. Datta
AU - R. Provvedi
AU - C. D. Sohaskey
AU - R. Ukey
AU - J. Puffal
AU - M. Prithviraj
AU - A. Tellez
AU - A. Saleh
AU - R. Khan
AU - R. Manganelli
AU - Y. S. Morita
AU - K. Y. Rhee
AU - M. L. Gennaro
PY - 2026
DA - 2026/09/09
PB - bioRxiv
DO - 10.64898/2026.09.09.750162
UR - https://www.biorxiv.org/content/10.64898/2026.09.09.750162v1
AB - Maintenance of membrane integrity and proton motive force (PMF) is critical for bacterial survival. The phage shock protein (Psp) system, conserved across bacterial species, stabilizes the membrane, maintains PMF, and protects against envelope damage. However, how the conserved effector PspA contributes to PMF maintenance remains unclear. Here, using the mycobacterial Psp system as a genetically tractable model, we provide mechanistic insight into this process. We show that PspA and the accessory protein PspM jointly sustain membrane potential, with PspM required to maintain a ~70 kDa PspA isoform at the membrane during envelope stress. Loss of PspA increases susceptibility to thioridazine, which targets type II NADH dehydrogenase (NDH-2), and to Ro 48-8071, an inhibitor of menaquinone biosynthesis. Notably, hypersusceptibility to thioridazine is rescued by exogenous menaquinone. Consistent with these phenotypes, a pspA-deficient mutant exhibits impaired NADH dehydrogenase activity despite unchanged abundance of NDH-2 and menaquinone (MK-9). Together, these findings identify a functional link between PspA and NADH dehydrogenase-dependent respiration and suggest that PspA contributes to PMF maintenance by supporting respiratory electron transfer.
ER -