Dec

ActA helps bacteria to disguise itself as a host cell organelle and escape from autophagy

written by cail • posted in Theory • 5,971 views • no comments

Bugs are smart!
Evolution always creates the perfect system for every single organism. Learn from them.
ActA not only drives bacterial motility; but also disguise them to survive inside host cells.

I am a little confused by the anti-aggregation activity of N terminus of ActA (Fig.4 and Fig.5) - are they trying to say that ActA anti-aggregates, thus prevents poly-ubiquitylation/autophagic recognition? And they are thinking that the anti-aggregating activity is by binding to Arp2/3 and Ena/VASP...

Very interesting paper!

F1000 review

Cristel Archambaud and Pascale Cossart
Institut Pasteur, France

How Listeria can subvert the host autophagy process to survive and disseminate is unclear. Here, Yoshikawa et al. provide an elegant work combining various approaches (microscopy, use of Listeria mutants, GFP [green fluorescent protein] constructs) to demonstrate that recruitment of the actin-related protein (Arp)2/3 complex and enabled/vasodilator-stimulated phosphoprotein (Ena/VASP), via the bacterial ActA surface protein, mediates Listeria escape from autophagic recognition.

Autophagy is a ubiquitous process used by cells to destroy unnecessary or damaged organelles and proteins. It is also an innate defense system used to eliminate invading cytoplasmic microorganisms. Although it was well-accepted that Listeria can escape autophagy, the molecular mechanisms and the virulence factors involved had remained controversial. In this work, Yoshikawa et al. have addressed the mechanism by which Listeria monocytogenes avoids autophagic recognition during infection. They demonstrated that, by exploiting the ability of ActA to recruit host cell cytoskeletal proteins, Listeria disguises itself as a host cell organelle, allowing it to survive. In this model, ActA-expressing bacteria are protected from ubiquitination and the recruitment of the p62 and LC3 proteins that are involved in the autophagosome formation. It will be important to elucidate which proteins are ubiquitinated on the bacterial surface. Are they really bacterial proteins or ubiquitinated host cell proteins? For further reading, see refs {1-5}, and also ref {6}, on which Pascale Cossart is an author.

References: {1} Deretic and Levine, Cell Host Microbe 2009, 5:527-49 [PMID: 19527881]. {2} Py et al. Autophagy 2007, 3:117-25 [PMID: 17204850]. {3} Rich et al. Cell Microbiol 2003, 5:455-68 [PMID: 12814436]. {4} Birmingham et al. Nature 2008, 451:350-4 [PMID: 18202661]. {5} Yano et al. Nature Immunol 2008, 9:908-16 [PMID: 18604211]. {6} Birmingham et al. Autophagy 2007, 3:442-51 [PMID: 17568179].

Nat Cell Biol. 2009 Oct;11(10):1233-40.

Listeria monocytogenes ActA-mediated escape from autophagic recognition.

Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M, Mimuro H, Nakagawa I, Yanagawa T, Ishii T, Kakizuka A, Sztul E, Chakraborty T, Sasakawa C.

Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo 108-8639, Japan.
Autophagy degrades unnecessary organelles and misfolded protein aggregates, as well as cytoplasm-invading bacteria. Nevertheless, the bacteria Listeria monocytogenes efficiently escapes autophagy. We show here that recruitment of the Arp2/3 complex and Ena/VASP, via the bacterial ActA protein, to the bacterial surface disguises the bacteria from autophagic recognition, an activity that is independent of the ability to mediate bacterial motility. L. monocytogenes expressing ActA mutants that lack the ability to recruit the host proteins initially underwent ubiquitylation, followed by recruitment of p62 (also known as SQSTM1) and LC3, before finally undergoing autophagy. The ability of ActA to mediate protection from ubiquitylation was further demonstrated by generating aggregate-prone GFP-ActA-Q79C and GFP-ActA-170(*) chimaeras, consisting of GFP (green fluorescent protein), the ActA protein and segments of polyQ or Golgi membrane protein GCP170 (ref. 6). GFP-ActA-Q79C and GFP-ActA-170(*) formed aggregates in the host cell cytoplasm, however, these ActA-containing aggregates were not targeted for association with ubiquitin and p62. Our findings indicate that ActA-mediated host protein recruitment is a unique bacterial disguise tactic to escape from autophagy.

PMID: 19749745