The molecular mechanism of induction of unfolded protein response by Chlamydia
| Autor: | Claudiu I. Bandea, Yusuf Omosun, Olga Stuchlik, Kahaliah Joseph, Zenas George, Carolyn M. Black, Joseph U. Igietseme, Jason M. Goldstein, Anthony A. Azenabor, Matthew S. Reed, James Partin, Francis O. Eko, Pavel Svoboda, Debra Ellerson, Jan Pohl, Qing He, Erika I. Lutter, Melissa A. McDonald |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chlamydia muridarum Myosin light-chain kinase Myosin ATPase Biophysics Chlamydia trachomatis Biochemistry Article Type three secretion system Mice 03 medical and health sciences 0302 clinical medicine Myosin Type III Secretion Systems Myosin II complex Animals Humans Molecular Biology Inclusion Bodies Myosin Type II Host Microbial Interactions Effector Chemistry Cell Biology Chlamydia Infections Myosin complex Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Unfolded Protein Response Unfolded protein response HeLa Cells |
| Zdroj: | Biochemical and Biophysical Research Communications. 508:421-429 |
| ISSN: | 0006-291X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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