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The Aggregatibacter  actinomycetemcomitans cytolethal distending toxin (Cdt) induces lymphocytes to undergo cell-cycle arrest and apoptosis; toxicity is dependent upon the active Cdt subunit, CdtB. We now demonstrate that p21 CIP1/WAF1 is critical to Cdt-induced apoptosis. Cdt induces increases in the levels of p21 CIP1/WAF1 in lymphoid cell lines, Jurkat and MyLa, and in primary human lymphocytes. These increases were dependent upon CdtB's ability to function as a phosphatidylinositol (PI) 3,4,5-triphosphate (PIP3) phosphatase. It is noteworthy that Cdt-induced increases in the levels of p21 CIP1/WAF1 were accompanied by a significant decline in the levels of phosphorylated p21 CIP1/WAF1 . The significance of Cdt-induced p21 CIP1/WAF1 increase was assessed by preventing these changes with a two-pronged approach; pre-incubation with the novel p21 CIP1/WAF1 inhibitor, UC2288, and development of a p21 CIP1/WAF1 -deficient cell line (Jurkat p21- ) using clustered regularly interspaced short palindromic repeats (CRISPR)/cas9 gene editing. UC2288 blocked toxin-induced increases in p21 CIP1/WAF1 , and Jurkat WT cells treated with this inhibitor exhibited reduced susceptibility to Cdt-induced apoptosis. Likewise, Jurkat p21- cells failed to undergo toxin-induced apoptosis. The linkage between Cdt, p21 CIP1/WAF1 , and apoptosis was further established by demonstrating that Cdt-induced increases in levels of the pro-apoptotic proteins Bid, Bax, and Bak were dependent upon p21 CIP1/WAF1 as these changes were not observed in Jurkat p21- cells. Finally, we determined that the p21 CIP1/WAF1 increases were dependent upon toxin-induced increases in the level and activity of the chaperone heat shock protein (HSP) 90. We propose that p21 CIP1/WAF1 plays a key pro-apoptotic role in mediating Cdt-induced toxicity.

The Cell-Cycle Regulatory Protein p21CIP1/WAF1 Is Required for Cytolethal Distending Toxin (Cdt)-Induced Apoptosis