The Secretion and Maturation Journey of Gingipains

ABSTRACT Multifunctional gingipains are trypsin‐like enzymes secreted extracellularly by Porphyromonas gingivalis , which require delicate transit and processing to be activated in different mature forms. This review manages to reconstruct each processing step including the specific cleavage sites and relative proteins or helpers. Errors in any steps can lead to the accumulation of immature gingipains and weaken the virulence of P. gingivalis . Of special note, we emphasize the contribution of new studies to the refinement of the gingipain maturation process and factors that influence their pathogenicity. For example, it is proposed that glutamine cyclase, which is responsible for cyclizing exposed glutamine to pyroglutamic acid after the N‐terminal signal peptide is removed, may be able to serve as a potential target for periodontitis treatment, as normal cyclization is key to maintaining the stability of gingipains. Further structural and functional unraveling of the type IX secretion system components, such as the identification of the structure of the PorV‐associated shuttle complex, the determination of PorZ's role as the A‐LPS deliverer, and the confirmation of the specific mechanism by which PorU promotes CTD removal and catalyzes the transpeptide reaction, has also contributed to a better understanding of gingipain processing. Meanwhile, as the successful activation of gingipains serves to fulfill their functions, this work also concentrates on gingipain pathogenicity, with a particular focus on how gingipains can induce or stimulate the development of systemic diseases, such as causing cardiovascular disorder through vascular damage or exacerbating inflammation in the brain in Alzheimer's disease after crossing the blood–brain barrier.