Effective killing of the human pathogen <i>Candida albicans</i> by a specific inhibitor of non‐essential mitotic kinesin Kip1p

Chua, Penelope; Roof, David M.; Lu, Yan; Sakowicz, Roman; Clarke, David J.; Pierce, Dan; Stephens, Thoryn; Hamilton, Matthew J.; Morgan, Brad; Morgans, David J.; Nakai, Takashi; Tomasi, Adam L.; Maxon, Mary E.

doi:10.1111/j.1365-2958.2007.05787.x

Cited by 18 publications

(29 citation statements)

References 55 publications

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“…It is possible that blebbistatin treatment traps myosin II on a fraction of SCVs/ Sifs, preventing its release by blocking its ATPase activity. A similar trapping of microtubule motors on their respective cytoskeletal filaments/cargo using specific drugs or nonhydrolyzable ATP analogues has been reported (9,14). The observation that myosin II can associate with SCVs/Sifs (albeit under artificial conditions) suggests that this motor acts locally at this compartment during infection.…”

Section: Discussionmentioning

confidence: 85%

Role for Myosin II in Regulating Positioning ofSalmonella-Containing Vacuoles and Intracellular Replication

et al. 2008

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Salmonella enterica serovar Typhimurium grows within host cells in a permissive compartment termed the Salmonella-containing vacuole (SCV). These bacteria use two distinct type III secretion systems (T3SS) to deliver virulence proteins (effectors) into cells. Effectors secreted by the Salmonella pathogenicity island 1 (SPI-1)-encoded T3SS mediate invasion and early SCV maturation steps, while those secreted by the SPI-2 T3SS affect the SCV at later stages postinfection. Some SPI-2 effectors modulate microtubule motor activity on the SCV. Here, we show that the actin-based motor myosin II also affects SCV dynamics during infection. Following invasion, myosin II is required for SCV positioning near the nucleus of host cells. Later, myosin II counteracts the activities of the SPI-2 effectors PipB2 and SseJ to maintain SCV positioning and stability, respectively. Myosin II activity was required for maximal bacterial growth in macrophages. Rho kinase activity was required for SCV positioning. The effector SopB, a known activator of Rho GTPases, was found to be required for SCV positioning, and transfection of cells with SopB was sufficient to induce myosin II phosphorylation. These studies reveal a novel role for myosin II in controlling SCV dynamics during infection and suggest that SopB activates myosin II.

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Section: Discussionmentioning

confidence: 85%

Role for Myosin II in Regulating Positioning ofSalmonella-Containing Vacuoles and Intracellular Replication

et al. 2008

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“…Kip1p was also inhibited by an aminobenzothiazole compound, which caused Kip1p to bind to microtubules in a rigor-like mechanism resulting in cell death. These studies reveal that drugs that target nonessential components of the microtubule apparatus can produce fungicidal effects, presumably due to arrest of the mitotic spindle, and thus are effective antifungal agents (14). It remains to be seen if similar studies of other kinesins, including Kar3p, will provide additional targets for antifungal drug discovery.…”

Section: Discussionmentioning

confidence: 99%

“…(63). In addition, Chua et al investigated the role of the kinesin Kip1p in C. albicans and showed that loss of Kip1p led to aberrant rounds of spindle pole body duplication, again accompanied by mitotic delay and elongated growth (14). Kip1p was also inhibited by an aminobenzothiazole compound, which caused Kip1p to bind to microtubules in a rigor-like mechanism resulting in cell death.…”

Section: Discussionmentioning

confidence: 99%

“…C. albicans yeast and pseudohyphal forms resemble those of S. cerevisiae, while the hyphal form is more analogous to true hyphal growth in filamentous fungi (11,13,32,44,57,62). There is a growing interest in the proteins that regulate mitotic events in C. albicans, as these represent targets for novel antifungal drugs (14,63). Recent studies have demonstrated that there is a single Kar3-like protein in C. albicans (8,31).…”

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confidence: 99%

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Microtubule Motor Protein Kar3 Is Required for Normal Mitotic Division and Morphogenesis in Candida albicans

Sherwood

Bennett

2008

Eukaryot Cell

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The kinesin-related protein Kar3 is a minus end-directed molecular motor that plays a multifunctional role in microtubule-directed nuclear movement. Previously, it was shown that Candida albicans Kar3p is critical for nuclear fusion during mating as kar3 mutants were defective in karyogamy. In this study, we confirm that Kar3p is required for nuclear congression in mating but that neither Kar3p nor the dynein motor protein Dyn1p is required for nuclear migration in the mating projection prior to cell fusion. In addition, we show that C. albicans Kar3p plays an important role in the cell and colony morphology of mitotically dividing cells, as evidenced by diminished filamentation of kar3 cells on Spider medium and an increased tendency of mutant cells to form pseudohyphal cells in liquid culture. Loss of Kar3p also led to defects in nuclear division, causing cells to grow slowly and exhibit reduced viability compared to wild-type cells. Slow growth was due, at least in part, to delayed cell cycle progression, as cells lacking Kar3p accumulated in anaphase of the cell cycle. Consistent with a role in mitotic division, Kar3 protein was shown to localize to the spindle pole bodies. Finally, kar3 cells exhibited unstable or aberrant mitotic spindles, a finding that accounts for the delay in cell cycle progression and decreased viability of these cells. We suggest that the altered morphology of kar3 cells is a direct consequence of the delay in anaphase, and this leads to increased polarized growth and pseudohypha formation.

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“…In all of these morphological states, microtubuleassociated motor proteins play major roles in microtubule cytoskeleton remodeling, nuclear movements, chromosome segregation, and cargo transport (7)(8)(9). This provides a rationale for their use as novel targets for antifungal drugs (10).…”

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confidence: 99%

Candida albicans Kinesin Kar3 Depends on a Cik1-Like Regulatory Partner Protein for Its Roles in Mating, Cell Morphogenesis, and Bipolar Spindle Formation

et al. 2015

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b Candida albicans is a major fungal pathogen whose virulence is associated with its ability to transition from a budding yeast form to invasive hyphal filaments. The kinesin-14 family member CaKar3 is required for transition between these morphological states, as well as for mitotic progression and karyogamy. While kinesin-14 proteins are ubiquitous, CaKar3 homologs in hemiascomycete fungi are unique because they form heterodimers with noncatalytic kinesin-like proteins. Thus, CaKar3-based motors may represent a novel antifungal drug target. We have identified and examined the roles of a kinesin-like regulator of CaKar3. We show that orf19.306 (dubbed CaCIK1) encodes a protein that forms a heterodimer with CaKar3, localizes CaKar3 to spindle pole bodies, and can bind microtubules and influence CaKar3 mechanochemistry despite lacking an ATPase activity of its own. Similar to CaKar3 depletion, loss of CaCik1 results in cell cycle arrest, filamentation defects, and an inability to undergo karyogamy. Furthermore, an examination of the spindle structure in cells lacking either of these proteins shows that a large proportion have a monopolar spindle or two dissociated half-spindles, a phenotype unique to the C. albicans kinesin-14 homolog. These findings provide new insights into mitotic spindle structure and kinesin motor function in C. albicans and identify a potentially vulnerable target for antifungal drug development. Candida albicans is a common commensal fungus that typically causes no harm to the host (1). However, in immunocompromised individuals, neonates, and patients under intensive care, it can cause serious skin and mucosal infections as well as life-threatening systemic infections (1, 2). It is also able to form tenacious biofilms on implanted medical devices (3). A major factor facilitating C. albicans virulence is its ability to readily switch between growth as a yeast, pseudohyphae, and hyphae (1, 4). In the yeast mode, daughter cells bud off and dissociate from the mother cell, while pseudohyphal cells remain connected at constricted septation sites (4). Hyphae are the invasive form and are important for virulence during systemic infections as well as for biofilm formation (1,5,6). In all of these morphological states, microtubuleassociated motor proteins play major roles in microtubule cytoskeleton remodeling, nuclear movements, chromosome segregation, and cargo transport (7-9). This provides a rationale for their use as novel targets for antifungal drugs (10).C. albicans Kar3 (CaKar3) is a kinesin-14 family member that has been shown to function in mitotic division and is critical for hypha formation and nuclear fusion during mating (9, 11). Its homolog in Saccharomyces cerevisiae has similar functions in mitosis and mating that are enabled by interactions with two kinesinlike proteins: S. cerevisiae Cik1 (ScCik1) and ScVik1 (12)(13)(14)(15)(16)(17)(18)(19)(20). ScKar3 forms complexes with each of these proteins via a central coiled-coil domain to form parallel heterodimers that are structurally ...

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Effective killing of the human pathogen Candida albicans by a specific inhibitor of non‐essential mitotic kinesin Kip1p

Cited by 18 publications

References 55 publications

Role for Myosin II in Regulating Positioning ofSalmonella-Containing Vacuoles and Intracellular Replication

Role for Myosin II in Regulating Positioning ofSalmonella-Containing Vacuoles and Intracellular Replication

Microtubule Motor Protein Kar3 Is Required for Normal Mitotic Division and Morphogenesis in Candida albicans

Candida albicans Kinesin Kar3 Depends on a Cik1-Like Regulatory Partner Protein for Its Roles in Mating, Cell Morphogenesis, and Bipolar Spindle Formation

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