D4-GDI, a Substrate of CPP32, Is Proteolyzed during Fas-induced Apoptosis

Abstract

Apoptosis (programmed cell death) is a fundamental process for normal development of multicellular organisms, and is involved in the regulation of the immune system, normal morphogenesis, and maintenance of homeostasis. ICE/CED-3 family cysteine proteases have been implicated directly in apoptosis, but relatively few of the substrates through which their action is mediated have been identified. Here we report that D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, is a substrate of the apoptosis protease CPP32/Yama/Apopain. D4-GDI was rapidly truncated to a

Cleavage and nuclear translocation of the caspase 3 substrate Rho GDP-dissociation inhibitor, D4-GDI, during apoptosis

“…The cleavage of D4-GDI at this site produces a protein that no longer regulates Rho, and the increased Rho activity may lead to the formation of toxic oxygen metabolites and increased inflammatory damage. The cleavage of D4-GDI by caspase 3-like activity has been detected during apoptosis induced by anti-FAS antibody, BAX, and staurosporine in Jurkat cells, 16,17 and anti IgM treatment of BL60 Burkitt lymphoma cells. 18 Inhibitors of caspases have been shown to inhibit this cleavage.…”

“…17 In vitro studies have shown that D4-GDI can be cleaved by caspase 3 after aspartate 19, and by caspase 1 after aspartate 54. 22 Monocytes release mature IL-1b after cleavage by caspase 1 and D4-GDI was found to be cleaved at the caspase 1 site in these cells.…”

“…The Rho family of small GTPases including Rho, Rac, and Cdc42, have been shown to regulate many cellular processes such as the assembly of the actin cytoskeleton and focal adhesions, 14 oxidant production in leukocytes, and the stress response through activation of cJun N-terminal kinase and p38 mpk2 . 15 Previously D4-GDI has been reported to be cleaved at aspartate 19 by caspase 3 during apoptosis in Jurkat Tcells induced with anti-Fas antibody, overexpression of Bax, and staurosporine, 16,17 and in BL60 Burkitt lymphoma cells induced with anti-IgM. 18 We add in this report the observations that D4-GDI is cleaved in ML-1 cells and many other cell types induced to undergo apoptosis by incubation with etoposide, staurosporine, or anti-fas antibody.…”

Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways

“…First, both Rac2 and CDC42 have been recently shown to be able to directly induce apoptosis when constitutively activated GTPases are introduced into transgenic T cells and Jurkat cells, respectively (Chuang et al, 1997;Lores et al, 1997). Second, it has been shown that D4-GDI, a hematopoietic cell regulator of CDC42/Rac is rapidly cleaved by Caspase 3 during Jurkat T cell apoptosis, implying that the disrupted regulation of CDC42/Rac by D4-GDI during apoptosis may transiently activate GTPases (Na et al, 1996). Third, CDC42/Rac have been demonstrated to activate the JNK signaling pathway which is also involved in apoptosis as demonstrated in PC12 cells (Xia et al, 1995) and JNK37/7 mice (Yang et al, 1997).…”

Caspases: the executioners of apoptosis

“…The biological significance of these proteolytic cleavages and their relationship with the ensuing apoptotic morphology is often not known. Caspase-3 is responsible, either wholly or in part, for the proteolytic cleavage of a large number of substrates during apoptosis, including PARP, DNA-dependent protein kinase (DNA-PK), U1-70 kDa, heteronuclear ribonucleoproteins C1 and C2, sterol regulatory binding proteins, D4-GDP dissociation inhibitor, huntingtin, and almost certainly retinoblastoma protein (Rb) [104][105][106][107][108][109][110][111] (Table 3). A common feature of all these substrates is the presence of a DXXD motif (Table 3), similar to that originally described in PARP [68].…”