Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival

Horn, Sebastian; Hughes, Michelle A.; Schilling, Ramon; Sticht, Carsten; Tenev, Tencho; Ploesser, Michaela; Meier, Pascal; Sprick, Martin R.; MacFarlane, Marion; Leverkus, Martin

doi:10.1016/j.celrep.2017.04.010

Cited by 92 publications

(63 citation statements)

References 52 publications

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“…However, at later timepoints (180 min), there were detectable, albeit low, levels of FLIP (L) at the DISC in CASP8 null cells, approximately half of which was in its unprocessed p55-form ( Fig 3A; lane 6). In agreement with the findings of others for the Fas/CD95 DISC [30], recruitment of procaspase-8's other paralog, procaspase-10, to the TRAIL-R2 DISC was also inhibited in the absence of procaspase-8; however, low amounts were again detectable at the latest timepoint. In isogenic HCT116 models lacking either procaspase-8, procaspase-10, or both, we further confirmed the importance of procaspase-8 for both FLIP and procaspase-10 recruitment (Figs 3B and EV5B).…”

Section: Flip(l) Inhibits Full Caspase-8 Activation When Equistoichiosupporting

confidence: 92%

A revised model of TRAIL ‐R2 DISC assembly explains how FLIP (L) can inhibit or promote apoptosis

et al. 2020

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The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase‐8 at death‐inducing signalling complexes (DISCs) formed by death receptors such as TRAIL‐R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase‐8) at which it converts from being anti‐ to pro‐apoptotic at the DISC. We also show that in the complete absence of FLIP(L), procaspase‐8 activation at the TRAIL‐R2 DISC has significantly slower kinetics, although ultimately the extent of apoptosis is significantly greater. This revised model of DISC assembly also explains why FLIP's recruitment to the TRAIL‐R2 DISC is impaired in the absence of caspase‐8 despite showing that it can interact with the DISC adaptor protein FADD and why the short FLIP splice form FLIP(S) is the more potent inhibitor of DISC‐mediated apoptosis.

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Section: Flip(l) Inhibits Full Caspase-8 Activation When Equistoichiosupporting

confidence: 92%

A revised model of TRAIL ‐R2 DISC assembly explains how FLIP (L) can inhibit or promote apoptosis

et al. 2020

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“…This has been confirmed in our lab using several CRISPR/Cas9 caspase‐8 knockout lines (D. B. Longley, unpublished observations). Interestingly, caspase‐10 has been recently shown to inhibit caspase‐8 activation, supporting earlier research that reported that the caspase‐8/‐10 heterodimer is inactive . Therefore, in overexpression models, caspase‐10 can induce cell death, whereas at physiologically relevant expression levels, it seems to inhibit caspase‐8‐mediated apoptosis.…”

Section: Canonical Flip Biology: Regulation Of Caspase‐8 Activationsupporting

confidence: 70%

FLIP as a therapeutic target in cancer

2018

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One of the classic hallmarks of cancer is disruption of cell death signalling. Inhibition of cell death promotes tumour growth and metastasis, causes resistance to chemo‐ and radiotherapies as well as targeted agents, and is frequently due to overexpression of antiapoptotic proteins rather than loss of pro‐apoptotic effectors. FLIP is a major apoptosis‐regulatory protein frequently overexpressed in solid and haematological cancers, in which its high expression is often correlated with poor prognosis. FLIP, which is expressed as long (FLIP(L)) and short (FLIP(S)) splice forms, achieves its cell death regulatory functions by binding to FADD, a critical adaptor protein which links FLIP to the apical caspase in the extrinsic apoptotic pathway, caspase‐8, in a number of cell death regulating complexes, such as the death‐inducing signalling complexes (DISCs) formed by death receptors. FLIP also plays a key role (together with caspase‐8) in regulating another form of cell death termed programmed necrosis or ‘necroptosis’, as well as in other key cellular processes that impact cell survival, including autophagy. In addition, FLIP impacts activation of the intrinsic mitochondrial‐mediated apoptotic pathway by regulating caspase‐8‐mediated activation of the pro‐apoptotic Bcl‐2 family member Bid. It has been demonstrated that FLIP can not only inhibit death receptor‐mediated apoptosis, but also cell death induced by a range of clinically relevant chemotherapeutic and targeted agents as well as ionizing radiation. More recently, key roles for FLIP in promoting the survival of immunosuppressive tumour‐promoting immune cells have been discovered. Thus, FLIP is of significant interest as an anticancer therapeutic target. In this article, we review FLIP's biology and potential ways of targeting this important tumour and immune cell death regulator.

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“…It is noteworthy that the murine gene for caspase‐10 is a pseudogene—raising questions about the physiological role of the human counterpart. Whether caspase‐10 can induce apoptosis in the absence of caspase‐8 is subject to debate, and one recent study even suggested that caspase‐10 has a potential inhibitory role (similar to that of FLIP) . In some cell types, the amount of active caspases‐8 and ‐10 is too low to directly activate the downstream executioner caspases (caspases‐3, ‐6 and ‐7).…”

Section: Lymphocyte Apoptosis: Extrinsic Versus Intrinsic Pathwaysmentioning

confidence: 99%

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia

Meynier

Rieux-Laucat

2018

Immunological Reviews

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Summary The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self‐regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self‐antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.

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Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival

Cited by 92 publications

References 52 publications

A revised model of TRAIL ‐R2 DISC assembly explains how FLIP (L) can inhibit or promote apoptosis

A revised model of TRAIL ‐R2 DISC assembly explains how FLIP (L) can inhibit or promote apoptosis

FLIP as a therapeutic target in cancer

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia

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