The molecular mechanism of induction of unfolded protein response by Chlamydia

• Published in: Biochemical and biophysical research communications 2019-01, Vol.508 (2), p.421-429
• Main Authors: George, Zenas, Omosun, Yusuf, Azenabor, Anthony A., Goldstein, Jason, Partin, James, Joseph, Kahaliah, Ellerson, Debra, He, Qing, Eko, Francis, McDonald, Melissa A., Reed, Matthew, Svoboda, Pavel, Stuchlik, Olga, Pohl, Jan, Lutter, Erika, Bandea, Claudiu, Black, Carolyn M., Igietseme, Joseph U.
• Format: Article
• Language: English
• Subjects: Animals; Chlamydia; Chlamydia Infections - etiology; Chlamydia Infections - metabolism; Chlamydia Infections - microbiology; Chlamydia muridarum - metabolism; Chlamydia muridarum - pathogenicity; Chlamydia trachomatis - metabolism; Chlamydia trachomatis - pathogenicity; HeLa Cells; Host Microbial Interactions - physiology; Humans; Inclusion Bodies - metabolism; Mice; Myosin II complex; Myosin Type II - metabolism; Pathogenesis; T3SS; Type III Secretion Systems - metabolism; Unfolded protein response; Unfolded Protein Response - physiology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.11.034

The unfolded protein response (UPR) contributes to chlamydial pathogenesis, as a source of lipids and ATP during replication, and for establishing the initial anti-apoptotic state of host cell that ensures successful inclusion development. The molecular mechanism(s) of UPR induction by Chlamydia is unknown. Chlamydia use type III secretion system (T3SS) effector proteins (e.g, the Translocated Actin-Recruiting Phosphoprotein (Tarp) to stimulate host cell's cytoskeletal reorganization that facilitates invasion and inclusion development. We investigated the hypothesis that T3SS effector-mediated assembly of myosin-II complex produces activated non-muscle myosin heavy chain II (NMMHC-II), which then binds the UPR master regulator (BiP) and/or transducers to induce UPR. Our results revealed the interaction of the chlamydial effector proteins (CT228 and Tarp) with components of the myosin II complex and UPR regulator and transducer during infection. These interactions caused the activation and binding of NMMHC-II to BiP and IRE1α leading to UPR induction. In addition, specific inhibitors of myosin light chain kinase, Tarp oligomerization and myosin ATPase significantly reduced UPR activation and Chlamydia replication. Thus, Chlamydia induce UPR through T3SS effector-mediated activation of NMMHC-II components of the myosin complex to facilitate infectivity. The finding provides greater insights into chlamydial pathogenesis with the potential to identify therapeutic targets and formulations. •Chlamydia induces UPR for ATP, nutrients and to protect host cell from apoptosis.•Chlamydial T3SS effectors activate non-muscle myosin heavy chain II (NMMHC-II).•Activated NMMHC-II binds UPR master regulator (BiP) or transducers to induce UPR.•Inhibition of UPR activation prevents Chlamydia replication and inclusion formation.