Artículo
Mycobacterium tuberculosis DosS binds H2S through its Fe3+ heme iron to regulate the DosR dormancy regulon
Sevalkar, Ritesh R.; Glasgow, Joel N.; Pettinati, Martín
; Marti, Marcelo Adrian
; Reddy, Vineel P.; Basu, Swati; Alipour, Elmira; Kim-Shapiro, Daniel B.; Estrin, Dario Ariel
; Lancaster, Jack R.; Steyn, Adrie J. C.
![Icon](/themes/CONICETDigital/images/conicet.png)
![Icon](/themes/CONICETDigital/images/conicet.png)
![Icon](/themes/CONICETDigital/images/conicet.png)
Fecha de publicación:
06/2022
Editorial:
Elsevier
Revista:
Redox Biology
ISSN:
2213-2317
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Mycobacterium tuberculosis (Mtb) senses and responds to host-derived gasotransmitters NO and CO via heme-containing sensor kinases DosS and DosT and the response regulator DosR. Hydrogen sulfide (H2S) is an important signaling molecule in mammals, but its role in Mtb physiology is unclear. We have previously shown that exogenous H2S can modulate expression of genes in the Dos dormancy regulon via an unknown mechanism(s). Here, we test the hypothesis that Mtb senses and responds to H2S via the DosS/T/R system. Using UV–Vis and EPR spectroscopy, we show that H2S binds directly to the ferric (Fe3+) heme of DosS (KDapp = 5.30 μM) but not the ferrous (Fe2+) form. No interaction with DosT(Fe2+-O2) was detected. We found that the binding of sulfide can slowly reduce the DosS heme iron to the ferrous form. Steered Molecular Dynamics simulations show that H2S, and not the charged HS− species, can enter the DosS heme pocket. We also show that H2S increases DosS autokinase activity and subsequent phosphorylation of DosR, and H2S-mediated increases in Dos regulon gene expression is lost in Mtb lacking DosS. Finally, we demonstrate that physiological levels of H2S in macrophages can induce DosR regulon genes via DosS. Overall, these data reveal a novel mechanism whereby Mtb senses and responds to a third host gasotransmitter, H2S, via DosS(Fe3+). These findings highlight the remarkable plasticity of DosS and establish a new paradigm for how bacteria can sense multiple gasotransmitters through a single heme sensor kinase.
Palabras clave:
DORMANCY REGULON
,
DOSS
,
HYDROGEN SULFIDE
,
TUBERCULOSIS
,
TWO-COMPONENT SYSTEM
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(INQUIMAE)
Articulos de INST.D/QUIM FIS D/L MATERIALES MEDIOAMB Y ENERGIA
Articulos de INST.D/QUIM FIS D/L MATERIALES MEDIOAMB Y ENERGIA
Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Citación
Sevalkar, Ritesh R.; Glasgow, Joel N.; Pettinati, Martín; Marti, Marcelo Adrian; Reddy, Vineel P.; et al.; Mycobacterium tuberculosis DosS binds H2S through its Fe3+ heme iron to regulate the DosR dormancy regulon; Elsevier; Redox Biology; 52; 6-2022; 1-12
Compartir
Altmétricas