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J. Exp. Med.,
Volume 189, Number 9, May 3, 1999 1479-1488
By
From the * Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale School of
Medicine, New Haven, Connecticut 06536-0812; and the Salmonella typhimurium has sustained a long-standing association with its host and therefore has
evolved sophisticated strategies to multiply and survive within this environment. Central to
Salmonella pathogenesis is the function of a dedicated type III secretion system that delivers bacterial effector proteins into the host cell cytoplasm. These effectors stimulate nuclear responses
and actin cytoskeleton reorganization leading to the production of proinflammatory cytokines
and bacterial internalization. The stimulation of these responses requires the function of Cdc42,
a member of the Rho family of small molecular weight GTPases, and SopE, a bacterial effector
protein that stimulates guanine nucleotide exchange on Rho GTPases. However, nothing is
known about the role of Cdc42 effector proteins in S. typhimurium-induced responses. We
showed here that S. typhimurium infection of cultured epithelial cells results in the activation of
p21-activated kinase (PAK), a serine/threonine kinase that is an effector of Cdc42-dependent responses. Transient expression of a kinase-defective PAK blocked both S. typhimurium- and
SopE-induced c-Jun NH2-terminal kinase (JNK) activation but did not interfere with bacteria-induced actin cytoskeleton rearrangements. Similarly, expression of SH3-binding mutants of
PAK did not block actin-mediated S. typhimurium entry into cultured cells. However, expression of an effector loop mutant of Cdc42Hs (Cdc42HsC40) unable to bind PAK and other
CRIB (for Cdc42/Rac interacting binding)-containing target proteins resulted in abrogation of both S. typhimurium-induced nuclear and cytoskeletal responses. These results show that PAK
kinase activity is required for bacteria-induced nuclear responses but it is not required for cytoskeletal rearrangements, indicating that S. typhimurium stimulates cellular responses through different Cdc42 downstream effector activities. In addition, these results demonstrate that the
effector loop of Cdc42 implicated in the binding of PAK and other CRIB-containing target
proteins is required for both responses.
Department of Pharmacology,
Cornell University, Ithaca, New York 14853
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