p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8<sup>+</sup> T Cells

Farley, Nicholas; Pedraza‐Alva, Gustavo; Serrano‐Gómez, Diego; Nagaleekar, Viswas Konasagara; Aronshtam, Alexander; Krahl, Troy; Thornton, Tina M.; Rincón, Mercedes

doi:10.1128/mcb.26.6.2118-2129.2006

Cited by 75 publications

(58 citation statements)

References 69 publications

(78 reference statements)

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“…Elevated expression of Bcl-xL prevents T cell death in response to cytokine withdrawal and Fas/FasL signaling (53)(54)(55). Our finding of lower Bcl-xL and higher FasL expression on Pdl1 -/-donor T cells during GVHD provides a downstream mechanism to explain the higher apoptosis and lower absolute capacity (after the subsequent addition of oligomycin to suppress mitochondrial ATP production) ( Figure 9, B and C).…”

Section: Discussionmentioning

confidence: 63%

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Saha¹,

O’Connor²,

Thangavelu³

et al. 2016

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 63%

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Saha¹,

O’Connor²,

Thangavelu³

et al. 2016

Journal of Clinical Investigation

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“…40 Interestingly, p38 was also reported to mediate a CD95-dependent mitochondrial death in T cells. 41 Our data show a physiologic role for HPK1-C as a potent mediator of the intrinsic cell death pathway involving Bim and suggest that HPK1-C determines the ratio between CD95/CD95L-dependent versus -independent AICD in T cells.…”

Section: Discussionmentioning

confidence: 95%

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Brenner

Golks

Becker

et al. 2007

Blood

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Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-κB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-κB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2–driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C se-lectively blocks induction of NF-κB–dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C–dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.

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“…Fas signaling leads to apoptosis through the p38 MAPK step (24), which may provide a mechanism for engagement of this stress kinase in the acantholytic pathway. Noteworthy, cell detachment/mechanical stress per se can trigger p38 MAPK, leading to overexpression of Fas ligand (25) and induction of Hsp27 and Hsp70 (26).…”

Section: Discussionmentioning

confidence: 99%

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Chernyavsky

Arredondo

Kitajima

et al. 2007

Journal of Biological Chemistry

128

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Although it is accepted that pemphigus antibody binding to keratinocytes (KCs) evokes an array of intracellular biochemical events resulting in cell detachment and death, the triggering events remain obscure. It has been postulated that the binding of pemphigus vulgaris IgG (PVIgG) to KCs induces "desmosomal" signaling. Because in contrast to integrins and classical cadherins, desmoglein (Dsg) molecules are not known to elicit intracellular signaling, and because PV patients also produce non-Dsg autoantibodies, we investigated the roles of both Dsg and non-desmoglein PV antigens. The time course studies of KCs treated with PVIgG demonstrated that the activity of Src peaked at 30 min, EGF receptor kinase (EGFRK) at 60 min, and p38 MAPK at 240 min. The Src inhibitor PP2 decreased EGFRK and p38 activities by ϳ45 and 30%, respectively, indicating that in addition to Src, PVIgG evokes other triggering events. The shrinkage of KCs (cell volume reduction) became significant at 120 min, keratin aggregation at 240 min, and an increase of TUNEL positivity at 360 min. Pretreatment of KCs with PP2 blocked PVIgG-dependent cell shrinkage and keratin aggregation by ϳ50% and TUNEL positivity by ϳ25%. The p38 MAPK inhibitor PD169316 inhibited these effects by ϳ15, 20, and 70%, respectively. Transfection of KCs with small interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked ϳ50% of p38 MAPK activity but did not significantly alter the PVIgG-dependent rise in Src and EGFRK activities. These results indicate that activation of p38 MAPK is a late signaling step associated with collapse of the cytoskeleton and disassembly of desmosomes caused by upstream events involving Src and EGFRK. Therefore, the early acantholytic events are triggered by non-Dsg antibodies.

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p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8⁺ T Cells

Cited by 75 publications

References 69 publications

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

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p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8+ T Cells

Cited by 75 publications

References 69 publications

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

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p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8⁺ T Cells