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PNAS 103 (26): 9897-9902

Copyright © 2006 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

A mechanism of cell death involving an adenylyl cyclase/PKA signaling pathway is induced by the Cry1Ab toxin of Bacillus thuringiensis

Xuebin Zhang*,{dagger}, Mehmet Candas*,{dagger}, Natalya B. Griko*,{dagger}, Ronald Taussig{ddagger}, and Lee A. Bulla, Jr.*,{dagger},§

*Biological Targets, Inc., Dallas, TX 75235; {dagger}Center for Biotechnology and Bioinformatics and Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083; and {ddagger}Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041

Communicated by Eugene W. Nester, University of Washington, Seattle, WA, May 17, 2006

Received for publication March 14, 2006.

Abstract: Many pathogenic organisms and their toxins target host cell receptors, the consequence of which is altered signaling events that lead to aberrant activity or cell death. A significant body of literature describes various molecular and cellular aspects of toxins associated with bacterial invasion, colonization, and host cell disruption. However, there is little information on the molecular and cellular mechanisms associated with the insecticidal action of Bacillus thuringiensis (Bt) Cry toxins. Recently, we reported that the Cry1Ab toxin produced by Bt kills insect cells by activating a Mg2+-dependent cytotoxic event upon binding of the toxin to its receptor BT-R1. Here we show that binding of Cry toxin to BT-R1 provokes cell death by activating a previously undescribed signaling pathway involving stimulation of G protein (G{alpha}s) and adenylyl cyclase, increased cAMP levels, and activation of protein kinase A. Induction of the adenylyl cyclase/protein kinase A pathway is manifested by sequential cytological changes that include membrane blebbing, appearance of ghost nuclei, cell swelling, and lysis. The discovery of a toxin-induced cell death pathway specifically linked to BT-R1 in insect cells should provide insights into how insects evolve resistance to Bt and into the development of new, safer insecticides.

Key Words: Cry toxin • protein kinase A • cadherin receptor • cAMP • signal transduction


Author contributions: X.Z., M.C., and L.A.B. designed research; X.Z., M.C., N.B.G., and L.A.B. performed research; R.T. contributed new reagents/analytic tools; X.Z., M.C., N.B.G., R.T., and L.A.B. analyzed data; and X.Z., M.C., and L.A.B. wrote the paper.

Conflict of interest statement: No conflicts declared.

§To whom correspondence should be addressed at: Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083-0688. E-mail: lee.bulla{at}utdallas.edu

© 2006 by The National Academy of Sciences of the USA


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