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Fig. 1. Needle complex of S. typhimurium type III secretion system. (A) Electron micrographs of osmotically shocked S. typhimurium showing needle complexes in the bacterial envelope (arrows). (B) Electron micrographs of purified needle complexes. (C) Schematic representation of the needle complex and its components. The location of the different components is hypothetical and more proteins may be present in the complex. [Figure reprintzed with permission from ref. 2 (Copyright 1999, American Association for the Advancement of Science).]

also to deliver them to the inside of the eukaryotic host cell. Perhaps a more important factor contributing to their complexity is the temporal and spatial restrictions that govern their activity. Thus, the function of type III secretion systems requires poorly characterized signals that cue the bacteria to secrete and deliver proteins at the appropriate time and in the appropriate environment.

A number of components of the type III secretion system assemble into an organelle, appropriately termed the “needle complex,” that spans both the inner and outer membranes of the bacterial envelope (ref.6; Fig. 1). The architecture of the needle complex resembles that of the flagellar hook-basal body (7, 8). It is composed of two pairs of inner and outer rings that presumably anchor the structure to the inner and outer membranes of the bacterial envelope. The rings are connected by a rod-like structure, which together form the base of the needle complex. A needle-like structure of ≈80 nm in length protrudes outwards from the base of the needle complex. The entire structure is ≈100 nm in length and ≈40 nm in diameter at its widest section. The identification of the needle complex has provided important clues in understanding the transit of type III secreted proteins through the bacterial envelope. However, this information has been less useful in elucidating the mechanisms by which this system mediates the translocation of the secreted proteins into the host cell. The latter process depends on the function of a subset of type III secreted proteins that, although dispensable for protein secretion, are essential for the translocation of effector proteins into the host cell. In Salmonella, those proteins are SipB, SipC, and SipD (9, 10, 11 and 12). The mechanisms by which these “protein translocases” mediate the delivery of effector proteins into the eukaryotic host cell are not understood. However, functionally equivalent proteins in other type III secretion systems (e.g., Yersinia spp.) have been proposed to form a pore or channel through which the effector proteins cross the eukaryotic cell membrane (13, 14).

Another important component of type III secretion systems is a family of small molecular weight acidic polypeptides that bind a specific subset of cognate cytosolic proteins (15). Although absolutely required for the function of the type III secretion systems, the actual mechanisms by which these proteins exert their chaperone-like function is poorly understood and is the subject of some controversy. At least two functions have been proposed for these proteins: (i) partitioning factors that prevent the premature association of type III secreted proteins within the bacterial cytoplasm, and ( ii) secretion pilots that “guide” the cognate secreted protein to the secretion machinery. It is possible that different chaperones may exert different functions. The Salmonella invasion-associated type III secretion system encodes at least three such chaperone-like proteins: SicP (16), SicA (12), and SigD (17, 18). SicP serves as chaperone for the effector protein SptP (16). Consistent with this role, SicP binds SptP, which in its absence completely is degraded within the bacterial cytoplasm. Thus, SicP seems to function as a partitioning factor for SptP, perhaps preventing it from interacting with an as-yet-unidentified protein. SicA, however, appears to play a more complex role (19). One of its functions is to prevent the association of SipB and SipC in the bacterial cytosol that would target these proteins for degradation. Absence of SicA results in the degradation of both SipB and SipC. Interestingly, in the absence of both SicA and SipC, SipB is not only stable but also is secreted at wild-type levels, indicating that SicA is not essential for SipB secretion per se. In addition, absence of SicA results in the lack of expression of several genes that encode type III effector proteins, suggesting another function for this protein (19). It is possible that some of the chaperones associated with type III secretion systems exert a role in the temporal regulation of substrate secretion by the secretion machinery. Indeed, evidence has been presented that indicates that there is a hierarchy in the secretion of type III proteins in Salmonella (20, 21).



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