Editors' ChoiceMicrobiology

Under Pathogen Attack

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Science's STKE  24 Jan 2006:
Vol. 2006, Issue 319, pp. tw32
DOI: 10.1126/stke.3192006tw32

Three independent groups report on the diverse mechanisms by which pathogens subvert cellular signaling processes to gain entry or permit infection. Li et al. report the crystal structure of simian virus 5 V protein (SV5-V) complexed with the DDB1 subunit of the cullin Cul4-based E3 ubiquitin ligase. V proteins of paramyxoviruses hijack the DDB1-Cul4-Roc1 E3 complex and direct the ubiquitination and degradation of STATs (signal transducers and activators of transcription), which stimulate the expression of antiviral genes in response to interferon. SV5-V binds to the pocket formed by two rigidly coupled seven-bladed β propeller domains of DDB1. A third β propeller domain that is more flexible associates with the Cul4 subunit. Binding of SV5-V alters the substrate recognition by the double propeller pocket, thereby targeting STATs, which are not substrates of this ubiquitin ligase in uninfected cells.

Alto et al. describe a new family of bacterial proteins that share a WxxxE motif. Individual overexpression of three members, IpgB1 and IpgB2 from Shigella and Map from E. coli, altered the actin cytoskeleton in the transfected cells. This effect appeared to result from the ability of these proteins to serve as guanosine triphosphatase (GTPase) mimics, regulating the activity of downstream effectors of Rho, Cdc42, and Rac. The bacterial proteins were not GTPases; instead, they interacted directly with downstream effectors. In a screen for binding partners, IpgB2, which induced the formation of new stress fibers when transfected into multiple cell types, interacted with the Rho-binding domain (called the GBD) of CRIK, a kinase regulated by binding to Rho. In transfected cells, IpgB2 interacted with the Rho-associated kinase ROCK. Whereas inhibition of Rho did not block stress fiber formation in response to IpgB2, inhibition of ROCK did. IpgB2 also interacted with GBD of the Rho effector mDia. Transfection of IpgB1 stimulated actin-rich membrane ruffles, reminiscent of those triggered by Rac. Overexpression of Map or infection of cells with the bacteria that produces Map caused the formation of filopodia, which is also a characteristic of Cdc42 activation. Further analysis showed that phosphorylation of the Rac and Cdc42 downstream effectors Jun N-terminal kinase (JNK) and c-jun was increased in Map-overexpressing cells. Inhibition of Rac or Cdc42 did not block Map-induced actin reorganization. However, coexpression of a C-terminal fragment (the VCA fragment) of the Wiscott-Aldrich syndrome protein (WASP) family, which are actin regulators through their interactions with the Arp2/3 complex, did block Map-induced actin reorganization. Map also contains a consensus PDZ binding motif and was found to interact with the ezrin binding protein 50 (EBP50, also known as NHERF). Map-induced actin reorganization was dependent on this interaction, which appeared to mediate subcellular targeting of Map. Thus, the WxxxE family of proteins appears to behave as selective GTPase mimics (see Hayward and Koronakis for commentary).

Coyne and Bergelson describe how coxsackievirus uses signaling processes initiated by decay-accelerating factor (DAF) to disrupt tight junctions and gain entry into epithelial cells. Group B coxsackieviruses (CVBs) are known to attach to epithelial cells at the CAR (coxsackievirus and adenovirus receptor), but this receptor is normally inaccessible because it is part of the tight junction complex. Although it was known that some CVB strains (or isolates) also interacted with DAF, a glycophospholipid-anchored protein that is exposed on the apical surface of epithelial cells, the functional consequence of that interaction was not clear. Coyne and Bergelson show that particular isolates of CVBs can bind DAF and trigger the redistribution of DAF and virus to punctate clusters, followed by movement of these clusters in a lipid raft-dependent fashion to the tight junction, where the virus colocalized with the CAR. Also required for delivery of the DAF-viral clusters to the tight junction was activation of the kinase Abl and Rac-stimulated remodeling of the actin cytoskeleton. Not only does the virus need to reach the tight junction, it must also be internalized and the viral particle must be uncoated. Virus-induced DAF clustering activated Src and Fyn, and Fyn activation was required for infection. Phosphorylation of the Fyn target caveolin was required for viral internalization at caveolae. Thus, DAF serves as an initial CVB receptor that delivers virus to the tight junction where the virus binds CAR; furthermore, DAF clustering stimulates the Rac pathway to reorganize the actin cytoskeleton and the Src family pathway to stimulate internalization.

T. Li, X. Chen, K. C. Garbutt, P. Zhou, N. Zheng, Structure of DDB1 in complex with a paramyxovirus V protein: Viral hijack of a propeller cluster in ubiquitin ligase. Cell 124, 105-117 (2006). [PubMed]

N. M. Alto, F. Shao, C. S. Lazar, R. L. Brost, G. Chua, S. Mattoo, S. A. McMahon, P. Ghosh, T. R. Hughes, C. Boone, J. E. Dixon, Identification of a bacterial type III effector family with G protein mimicry functions. Cell 124, 133-145 (2006). [PubMed]

R. D. Hayward, V. Koronakis, Pathogens reWritE Rho's rules. Cell 124, 15-17 (2006). [PubMed]

C. B. Coyne, J. M. Bergelson, Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124, 119-131 (2006). [PubMed]

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