Ras, Rap, and Rac Small GTP-binding Proteins Are Targets for Clostridium sordellii Lethal Toxin Glucosylation

Popoff, Michel R.; Chaves-Olarte, Esteban; Lemichez, Emmanuel; Eichel‐Streiber, Christoph von; Thelestam, Mónica; Chardin, Pierre Teilhard de; Cussac, Didier; Antonny, Bruno; Chavrier, Philippe; Flatau, Gilles; Giry, Murielle; Gunzburg, Jean de; Boquet, Patrice

doi:10.1074/jbc.271.17.10217

Cited by 201 publications

(166 citation statements)

References 30 publications

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“…The biological function of Rap1 is still unclear, but it has been proposed that activation of this small GTPase may feed into MAPK signaling pathways (50). As an approach to establishing if Rap1 has a role in cyclic AMPmediated delay of neutrophil apoptosis, we have blocked Rap1 activity using the Clostridium sordellii lethal toxin, which has been reported to inhibit specifically the small GTPases Rap1, Ras, and Rac (51). Furthermore, we have tested GGTI-286, a geranylgeranyltransferase inhibitor, which blocks geranylgeranylation required by Rap1 to achieve its mature, biologically active form (52).…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway

Martin

Dransfield

Haslett

et al. 2001

Journal of Biological Chemistry

102

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The second messenger molecule cyclic AMP dramatically modulates the apoptotic program in a wide variety of cells, accelerating apoptosis in some and delaying the rate of apoptosis in others. Human neutrophil apoptosis, a process that regulates the fate and numbers of these potentially histotoxic cells in inflammatory sites, is profoundly delayed by the cell-permeable analog of cyclic AMP, dibutyryl-cAMP. We have investigated the mechanisms underlying cyclic AMP-mediated delay of neutrophil apoptosis, and we show that cyclic AMP inhibits loss of mitochondrial potential occurring during constitutive neutrophil apoptosis. Furthermore, we demonstrate that cyclic AMP also suppresses caspase activation in these inflammatory cells. Despite increasing protein kinase A activity, this kinase is unlikely to mediate the effect of cyclic AMP on apoptosis because blockade of protein kinase A activation did not influence the survival effects of cyclic AMP. Further investigation of the signaling mechanism demonstrated that the delay of apoptosis is independent of phosphoinositide 3-kinase and MAPK activation. Our results suggest cyclic AMP delays neutrophil apoptosis via a novel, reversible, and transcriptionally independent mechanism. We show that proteasome activity in the neutrophil is vitally involved in this process, and we suggest that a balance of pro-apoptotic and anti-apoptotic proteins plays a key role in the powerful ability of cyclic AMP to delay neutrophil death.

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Section: Discussionmentioning

confidence: 99%

Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway

Martin

Dransfield

Haslett

et al. 2001

Journal of Biological Chemistry

102

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“…Of the kinases shown, only MKK7 and JNK1 have been shown to be activated in vivo [42,43]. which glucosylates and thereby inactivates Ras, Rac, and Rap [51]. We have found that LT inhibits p38 and p42/p44 MAP kinase activation by IL-1 in EL4 cells [52].…”

Section: Is a Low-molecular-weight G Protein Involved In Il-1 Signaling?mentioning

confidence: 99%

Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants

O’Neill

Greene

1998

Journal of Leukocyte Biology

525

343

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“…The family of large clostridial cytotoxins inactivate small GTPases by glucosylation (28). Whereas Clostridium difficile toxins A and B monoglucosylate Rho GTPases including Rho, Rac, and Cdc42 at Thr-37 or Thr-35, respectively (29), the lethal toxin from Clostridium sordellii modifies Rac, possibly Cdc42, but not Rho (30,31). In addition, Ras subfamily proteins (e.g.…”

Section: Cross-linking Of the High Affinity Ige Receptor (Fc⑀ri)mentioning

confidence: 99%

Inhibition of Calcium Release-activated Calcium Current by Rac/Cdc42-inactivating Clostridial Cytotoxins in RBL Cells

Djouder¹,

Prepens²,

Aktories³

et al. 2000

Journal of Biological Chemistry

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Using large clostridial cytotoxins as tools, the role of Rho GTPases in activation of RBL 2H3 hm1 cells was studied. Clostridium difficile toxin B, which glucosylates Rho, Rac, and Cdc42 and Clostridium sordellii lethal toxin, which glucosylates Rac and Cdc42 but not Rho, inhibited the release of hexosaminidase from RBL cells mediated by the high affinity antigen receptor (Fc⑀RI entry is suggested to depend on the depletion of intracellular Ca 2ϩ stores and is termed capacitative Ca 2ϩ entry (for review, see Refs. 7 and 8). The inward Ca 2ϩ current in RBL cells that seems to contribute to this entry is designated I CRAC for calcium release-activated calcium current. However, the regulatory mechanisms leading to activation of I CRAC is still unclear. Small GTPases have been suggested to participate in receptormediated Ca 2ϩ influx in RBL cells and mast cells (9). The small GTPases of the Rho family including Rho, Rac, and Cdc42 play important roles in regulation of the actin cytoskeleton (10). RhoA participates in growth factor-mediated formation of stress fibers and cell adhesions (11), Rac regulates membranes ruffling and lamellipodia (12) Recently, various bacterial toxins have been established as tools to study the function of small GTPases (23). Clostridium botulinum C3 transferase and related C3-like exoenzymes, including the C3 chimeric toxin C2IN-C3, selectively ADP-ribosylate RhoA, RhoB, and RhoC at Asn-41, thereby inhibiting their biological functions (24 -27). The family of large clostridial cytotoxins inactivate small GTPases by glucosylation (28). Whereas Clostridium difficile toxins A and B monoglucosylate Rho GTPases including Rho, Rac, and Cdc42 at Thr-37 or respectively (29), the lethal toxin from Clostridium sordellii modifies Rac, possibly Cdc42, but not Rho (30, 31). In addition, Ras subfamily proteins (e.g. Ras, Ral, and Rap) are glucosylated by the lethal toxin.Here we studied the effects of toxins on degranulation, Ca 2ϩ mobilization, and I CRAC in RBL 2H3 hm1 cells. We report that toxin B and lethal toxin but not the Rho-modifying chimeric toxin C2IN-C3 inhibit secretion and increase of [Ca 2ϩ ] i by the Fc⑀RI receptor in RBL cells. Moreover, the toxins inhibit thapsigargin-induced Ca 2ϩ mobilization and the activation of I CRAC by depletion of intracellular Ca 2ϩ stores, indicating that Rac/ Cdc42 but not Rho participates in regulation of capacitative Ca 2ϩ entry.* This work was supported by grants from the Deutsche Forschungsgemeinschaft (to K. A. and A. C.) and a grant from the BMBF (clinical research group "Pathomechanismen der allergischen Entzü ndung" (to K. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ To whom correspondence should be addressed: Inst. fü r Pharmakologie und Toxikologie, Albert-Ludwigs-Universitä t Freiburg, Hermann-Herder-Str. 5, 1 The abbreviations used are: Fc⑀RI, high affini...

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Ras, Rap, and Rac Small GTP-binding Proteins Are Targets for Clostridium sordellii Lethal Toxin Glucosylation

Cited by 201 publications

References 30 publications

Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway

Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway

Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants

Inhibition of Calcium Release-activated Calcium Current by Rac/Cdc42-inactivating Clostridial Cytotoxins in RBL Cells

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