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Final Ninghai Thesis final .pdf (4.31 MB)

MODULATION OF THE HOST UBIQUITIN MACHINERY BY LEGIONELLA PNEUMOPHILA EFFECTORS

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posted on 2019-08-13, 19:19 authored by Ninghai GanNinghai Gan

The bacterial pathogen Legionella pneumophila modulates host immunity using effectors translocated by its Dot/Icm transporter to facilitate its intracellular replication. A number of these effectors employ diverse mechanisms to interfere with protein ubiquitination, a post-translational modification essential for immunity. Here, we have found that L. pneumophila induces monoubiquitination of the E2 enzyme UBE2N by its Dot/Icm substrate MavC(Lpg2147). Ubiquitination of UBE2N by MavC abolishes its activity in the formation of K63-linked polyubiquitin chains, which dampens NF-kB signaling in the initial phase of bacterial infection. The inhibition of UBE2N activity by MavC creates a conundrum because this E2 enzyme is important in multiple signaling pathways, including some that are important for intracellular L. pneumophila replication. Here we also show that the activity of UBE2N is restored by MvcA(Lpg2148), an ortholog of MavC. MvcA functions to deubiquitinate UBE2N-Ub using the same catalytic triad required for its deamidase activity. Structural analysis of the MvcA-UBE2N-Ub complex reveals a crucial role of the insertion domain in MvcA in substrate recognition. Our findings reveal that two remarkably similar proteins catalyze the forward and reverse reactions to impose temporal regulation of the activity of UBE2N during L. pneumophila infection.

History

Degree Type

  • Doctor of Philosophy

Department

  • Biological Sciences

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Dr. Zhao-Qing Luo

Additional Committee Member 2

Dr. Daoguo Zhou

Additional Committee Member 3

Dr. Peter Hollenbeck

Additional Committee Member 4

Dr. Daniel Suter

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