The Bacteroidetes Q-rule and glutaminyl cyclase activity increase the stability of extracytoplasmic proteins

Katarzyna Szczęśniak, Florian Veillard, Carsten Scavenius, Kamila Chudzik, Kinga Ferenc, Matthias Bochtler, Jan Potempa*, Danuta Mizgalska*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review


In Gram-negative didermal species of the phylum Bacteroidetes, the majority of pre(pro)proteins exported across the cell membrane via the Sec system follow the Q-rule: a glutamine residue immediately downstream of a leader peptide is exposed as the new amino terminus by type I signal peptidases and converted to a pyroglutamate (also called oxyproline) residue by an inner membrane-associated glutaminyl cyclase (QC). Here, we show that the QC from Porphyromonas gingivalis is essential for growth in laboratory culture conditions. The lethal phenotype of QC deletion could not be rescued by an inactive variant of the enzyme, but it was rescued by QC orthologues from other species, despite their drastically lower activity toward a fluorescent reporter substrate. Replacement of glutamine after the signal peptide by an asparagine residue in selected QC substrates did not affect P. gingivalis viability but reduced the abundance of these proteins. Our data show that glutaminyl cyclization stabilizes P. gingivalis proteins, presumably protecting them from degradation by aminopeptidases. Loss of this protection is tolerated in individual substrates, but the complete loss in all Q-rule substrates is lethal, even in the absence of pressure from a host immune system. IMPORTANCE Exclusively in the Bacteroidetes phylum, most proteins exported across the inner membrane via the Sec system and released into the periplasm by type I signal peptidase have N-terminal glutamine converted to pyroglutamate. The reaction is catalyzed by the periplasmic enzyme glutaminyl cyclase (QC), which is essential for the growth of Porphyromonas gingivalis and other periodontopathogens. Apparently, pyroglutamyl formation stabilizes extracytoplasmic proteins and/or protects them from proteolytic degradation in the periplasm. Given the role of P. gingivalis as the keystone pathogen in periodontitis, P. gingivalis QC is a promising target for the development of drugs to treat and/or prevent this highly prevalent chronic inflammatory disease leading to tooth loss and associated with severe systemic diseases.

Antal sider16
StatusUdgivet - okt. 2023


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