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Anthrax is a lethal disease caused by the Gram-positive spore-producing bacterium  Bacillus anthracis . We previously demonstrated that disruption of  htrA  gene, encoding the chaperone/protease HtrA BA  (High Temperature Requirement A of  B. anthracis ) results in significant virulence attenuation, despite unaffected ability of Δ htrA  strains (in which the  htrA  gene was deleted) to synthesize the key anthrax virulence factors: the exotoxins and capsule.  B. anthracis  Δ htrA  strains exhibited increased sensitivity to stress regimens as well as silencing of the secreted starvation-associated Neutral Protease A (NprA) and down-modulation of the bacterial S-layer. The virulence attenuation associated with disruption of the  htrA  gene was suggested to reflect the susceptibility of Δ htrA  mutated strains to stress insults encountered in the host indicating that HtrA BA  represents an important  B. anthracis  pathogenesis determinant. As all HtrA serine proteases, HtrA BA  exhibits a protease catalytic domain and a PDZ domain. In the present study we interrogated the relative impact of the proteolytic activity (mediated by the protease domain) and the PDZ domain (presumably necessary for the chaperone activity and/or interaction with substrates) on manifestation of phenotypic characteristics mediated by HtrA BA . By inspecting the phenotype exhibited by Δ htrA  strains  trans -complemented with either a wild-type, truncated (ΔPDZ), or non-proteolytic form (mutated in the catalytic serine residue) of HtrA BA , as well as strains exhibiting modified chromosomal alleles, it is shown that (i) the proteolytic activity of HtrA BA  is essential for its N-terminal autolysis and subsequent release into the extracellular  milieu , while the PDZ domain was dispensable for this process, (ii) the PDZ domain appeared to be dispensable for most of the functions related to stress resilience as well as involvement of HtrA BA  in assembly of the bacterial S-layer, (iii) conversely, the proteolytic activity but not the PDZ domain, appeared to be dispensable for the role of HtrA BA  in mediating up-regulation of the extracellular protease NprA under starvation stress, and finally (iv) in a murine model of anthrax, the HtrA BA  PDZ domain, was dispensable for manifestation of  B. anthracis  virulence. The unexpected dispensability of the PDZ domain may represent a unique characteristic of HtrA BA  amongst bacterial serine proteases of the HtrA family.

Distinct Contribution of the HtrA Protease and PDZ Domains to Its Function in Stress Resilience and Virulence of Bacillus anthracis