TY  - JOUR
A1  - Wu, Yu
A1  - Pons, Valérie
A1  - Goudet, Amélie
A1  - Panigai, Laetitia
A1  - Fischer, Annette
A1  - Herweg, Jo-Ana
A1  - Kali, Sabrina
A1  - Davey, Robert A.
A1  - Laporte, Jérôme
A1  - Bouclier, Céline
A1  - Yousfi, Rahima
A1  - Aubenque, Céline
A1  - Merer, Goulven
A1  - Gobbo, Emilie
A1  - Lopez, Roman
A1  - Gillet, Cynthia
A1  - Cojean, Sandrine
A1  - Popoff, Michel R.
A1  - Clayette, Pascal
A1  - Le Grand, Roger
A1  - Boulogne, Claire
A1  - Tordo, Noël
A1  - Lemichez, Emmanuel
A1  - Loiseau, Philippe M.
A1  - Rudel, Thomas
A1  - Sauvaire, Didier
A1  - Cintrat, Jean-Christophe
A1  - Gillet, Daniel
A1  - Barbier, Julien
T1  - ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments
JF  - Scientific Reports
N2  - Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identifed the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efciently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.
KW  - biology
KW  - antimicrobials
KW  - high-throughput screening
KW  - infectious diseases
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173170
VL  - 7
ER  - 
TY  - JOUR
A1  - Fischer, Annette
A1  - Harrison, Kelly S
A1  - Ramirez, Yesid
A1  - Auer, Daniela
A1  - Chowdhury, Suvagata Roy
A1  - Prusty, Bhupesh K
A1  - Sauer, Florian
A1  - Dimond, Zoe
A1  - Kisker, Caroline
A1  - Hefty, P Scott
A1  - Rudel, Thomas
T1  - Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense
JF  - eLife
N2  - Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNγ and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.
KW  - cell-autonomous defense
KW  - Chlamydia trachomatis
KW  - deubiquitinase
KW  - Mcl-1
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171073
VL  - 6
IS  - e21465
ER  - 
TY  - JOUR
A1  - Auer, Daniela
A1  - Hügelschäffer, Sophie D.
A1  - Fischer, Annette B.
A1  - Rudel, Thomas
T1  - The chlamydial deubiquitinase Cdu1 supports recruitment of Golgi vesicles to the inclusion
JF  - Cellular Microbiology
N2  - Chlamydia trachomatis is the main cause of sexually transmitted diseases worldwide. As obligate intracellular bacteria Chlamydia replicate in a membrane bound vacuole called inclusion and acquire nutrients for growth and replication from their host cells. However, like all intracellular bacteria, Chlamydia have to prevent eradication by the host's cell autonomous system. The chlamydial deubiquitinase Cdu1 is secreted into the inclusion membrane, facing the host cell cytosol where it deubiquitinates cellular proteins. Here we show that inactivation of Cdu1 causes a growth defect of C. trachomatis in primary cells. Moreover, ubiquitin and several autophagy receptors are recruited to the inclusion membrane of Cdu1‐deficient Chlamydia . Interestingly, the growth defect of cdu1 mutants is not rescued when autophagy is prevented. We find reduced recruitment of Golgi vesicles to the inclusion of Cdu1 mutants indicating that vesicular trafficking is altered in bacteria without active deubiquitinase (DUB). Our work elucidates an important role of Cdu1 in the functional preservation of the chlamydial inclusion surface.
KW  - autophagy
KW  - Cdu1
KW  - ChlaDUB1
KW  - Chlamydia trachomatis
KW  - DUB
KW  - Golgi
KW  - xenophagy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208675
VL  - 22
IS  - 5
ER  -