Neutrophil degranulation is important in many inflammatory disorders, although the intracellular mechanisms underlying this process remain poorly understood. The Rho GTPase, Rac2, has been implicated in control of degranulation in earlier studies. We hypothesized that Rac2 selectively regulates neutrophil primary granule release. Using bone marrow and peritoneal exudate neutrophils from rac2(-/-) mice in comparison with similar cells from wild-type C57Bl/6 mice, we found that primary granule myeloperoxidase and elastase release was absent in Rac2(-/-) neutrophils in response to chemoattractant stimulation, cytochalasin B/f-Met-Leu-Phe (CB/fMLP), and CB/leukotriene B4. Rac2(-/-) neutrophils also failed to exhibit mobilization of the primary granule marker CD63+ during CB/fMLP stimulation as determined by confocal microscopy. Priming of Rac2(-/-) neutrophils with tumor necrosis factor (TNF) or by peritoneal elicitation did not rescue the defect in primary granule release. However, phosphorylation of p38 mitogen-activated protein (MAP) kinase in Rac2(-/-) neutrophils was evident in response to CB/fMLP and/or TNF. Primary granule density and morphology were normal in Rac2(-/-) neutrophils. Secondary specific and tertiary granule release, measured by lactoferrin immunoassay and zymography, was normal in response to CB/fMLP and adhesion to fibronectin. These findings suggest an obligatory role for Rac2 in regulation of primary granule release by neutrophils.
Background: How the mitotic checkpoint is silenced is not fully understood. Results: Interference with TRIP13 AAA-ATPase causes delayed activation of the anaphase-promoting complex/cyclosome and stalled metaphase-to-anaphase transition. Conclusion: TRIP13 is a novel mitotic checkpoint-silencing protein.Significance: TRIP13 overexpression may lead to premature chromosome segregation and chromosomal instability.
The mitotic checkpoint protein Spindly is farnesylated in vivo and this modification is required for its interaction with the RZZ complex and its localization to kinetochores.
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