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Goethe University Frankfurt, Max Planck Institute of Biophysics

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Mol. Cell, Published : November 12, 2019 | DOI:https://doi.org/10.1016/j.molcel.2019.10.019 Regulation of phosphoribosyl-linked serine ubiquitination by deubiquitinases DupA and DupB

Donghyuk Shin,^1,2,3,8 Rukmini Mukherjee,^1,2,8 Yaobin Liu,^1,2,8Alexis Gonzalez,^1,2 Florian Bonn,¹Yan Liu,⁴Vladimir V. Rogov,⁵ Marcel Heinz,^3,6 Alexandra Stolz,^1,2 Gerhard Hummer,^3,6 Volker Dötsch,⁵ Zhao-Qing Luo,⁴Sagar Bhogaraju,^1,2,7 and Ivan Dikic^1,2,3,9,*

¹Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
² Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
³ Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt am Main, Germany
⁴Purdue Institute of Immunology, Inflammation, and Infectious Diseases and Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
⁵ Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt, Germany
⁶ Institute of Biophysics, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany
⁷ European Molecular Biology Laboratory, 71 Avenue des Martyrs, 38000 Grenoble, France
⁸These authors contributed equally
⁹ Lead Contact

^*Correspondence : Ivan Dikic

Abstract

The family of bacterial SidE enzymes catalyzes non-canonical phosphoribosyl-linked (PR) serine ubiquitination and promotes infectivity of Legionella pneumophila. Here, we describe identification of two bacterial effectors that reverse PR ubiquitination and are thus named deubiquitinases for PR ubiquitination (DUPs; DupA and DupB). Structural analyses revealed that DupA and SidE ubiquitin ligases harbor a highly homologous catalytic phosphodiesterase (PDE) domain. However, unlike SidE ubiquitin ligases, DupA displays increased affinity to PR-ubiquitinated substrates, which allows DupA to cleave PR ubiquitin from substrates. Interfering with DupA-ubiquitin binding switches its activity toward SidE-type ligase. Given the high affinity of DupA to PR-ubiquitinated substrates, we exploited a catalytically inactive DupA mutant to trap and identify more than 180 PR-ubiquitinated host proteins in Legionella-infected cells. Proteins involved in endoplasmic reticulum (ER) fragmentation and membrane recruitment to Legionella-containing vacuoles (LCV) emerged as major SidE targets. The global map of PR-ubiquitinated substrates provides critical insights into host-pathogen interactions during Legionella infection.

논문정보

형식Research article
게재일2019년 11월 (BRIC 등록일 2019-11-15)
연구진국외 연구진
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