An incoherent feedforward loop formed by SirA/BarA, HilE and HilD is involved in controlling the growth cost of virulence factor expression by Salmonella Typhimurium
Por:
Perez-Morales, Deyanira, Nava-Galeana, Jessica, Rosales-Reyes, Roberto, Teehan, Paige, Yakhnin, Helen, Melchy-Perez, Erika I., Rosenstein, Yvonne, De la Cruz, Miguel A., Babitzke, Paul, Bustamante, Victor H.
Publicada:
1 may 2021
Resumen:
An intricate regulatory network controls the expression of Salmonella
virulence genes. The transcriptional regulator HilD plays a central role
in this network by controlling the expression of tens of genes mainly
required for intestinal colonization. Accordingly, the expression of
HilD is highly regulated by multiple factors, such as the SirA/BarA
two-component system and the Hcp-like protein HilE. SirA/BarA positively
regulates translation of hilD mRNA through a regulatory cascade
involving the small RNAs CsrB and CsrC, and the RNA-binding protein
CsrA, whereas HilE inhibits HilD activity by protein-protein
interaction. In this study, we show that SirA/BarA also positively
regulates translation of hilE mRNA through the same mentioned regulatory
cascade. Thus, our results reveal a paradoxical regulation exerted by
SirA/BarA-Csr on HilD, which involves simultaneous opposite effects,
direct positive control and indirect negative control through HilE. This
kind of regulation is called an incoherent type-1 feedforward loop
(I1-FFL), which is a motif present in certain regulatory networks and
represents a complex biological problem to decipher. Interestingly, our
results, together with those from a previous study, indicate that HilE,
the repressor component of the I1-FFL reported here
(I1-FFLSirA/BarA-HilE-HilD), is required to reduce the growth cost
imposed by the expression of the genes regulated by HilD. Moreover, we
and others found that HilE is necessary for successful intestinal
colonization by Salmonella. Thus, these findings support that
I1-FFLSirA/BarA-HilE-HilD cooperates to control the precise amount and
activity of HilD, for an appropriate balance between the growth cost and
the virulence benefit generated by the expression of the genes induced
by this regulator. I1-FFLSirA/BarA-HilE-HilD represents a complex
regulatory I1-FFL that involves multiple regulators acting at distinct
levels of gene expression, as well as showing different connections to
the rest of the regulatory network governing Salmonella virulence.
Author summary To infect the intestine of a broad range of hosts,
including humans, Salmonella is required to express a large number of
genes encoding different cellular functions, which imposes a growth
penalty. Thus, Salmonella has developed complex regulatory mechanisms
that control the expression of virulence genes. Here we identified a
novel and sophisticated regulatory mechanism that is involved in the
fine-tuned control of the expression level and activity of the
transcriptional regulator HilD, for the appropriate balance between the
growth cost and the virulence benefit generated by the expression of
tens of Salmonella genes. This mechanism forms an incoherent type-1
feedforward loop (I1-FFL), which involves paradoxical regulation; that
is, a regulatory factor exerting simultaneous opposite control (positive
and negative) on another factor. I1-FFLs are present in regulatory
networks of diverse organisms, from bacteria to humans, and represent a
complex biological problem to decipher. Interestingly, the I1-FFL
reported here is integrated by ancestral regulators and by regulators
that Salmonella has acquired during evolution. Thus, our findings reveal
a novel I1-FFL of bacteria, which is involved in virulence. Moreover,
our results illustrate the integration of ancestral and acquired factors
into a regulatory motif, which can lead to the expansion of regulatory
networks.
Filiaciones:
Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico
Consejo Nacional de Ciencia y Tecnología, Ciudad de México, Mexico
Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Department of Biochemistry and Molecular Biology, Center for RNA Molecular Biology, The Pennsylvania State University, University Park, PA, United States
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Hospital de Pediatria, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
Green Published, gold, All Open Access; Gold
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