The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers #

Schüngel, Sven; Buitrago‐Molina, Laura Elisa; Nalapareddy, Padmavathi devi; Lebofsky, Margitta; Manns, Michael P.; Jaeschke, Hartmut; Gross, Atan; Vogel, Arndt

doi:10.1002/hep.23176

Cited by 38 publications

(25 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…67 For example, in mice deficient for Bid, an injection of MegaFasL induced killing of parenchymal and possibly non-parenchymal cells within the liver, thereby driving hepatocellular demise and death of experimental animals, although the fatal outcome was still clearly delayed compared with wild-type mice. 67 This finding demonstrates that high level caspase-8-mediated activation of effector caspases, achieved by extensive Fas crosslinking on the cell surface, can bypass the need for the Bid4Bax/ Bak4MOMP amplification loop in type 2 cells, and this is consistent with the notion that XIAP acting as an inhibitor of effector caspases can regulate this process (see below).…”

Section: The Death Receptor Fasmentioning

confidence: 99%

Fas death receptor signalling: roles of Bid and XIAP

2011

View full text Add to dashboard Cite

Fas (also called CD95 or APO-1), a member of a subgroup of the tumour necrosis factor receptor superfamily that contain an intracellular death domain, can initiate apoptosis signalling and has a critical role in the regulation of the immune system. Fas-induced apoptosis requires recruitment and activation of the initiator caspase, caspase-8 (in humans also caspase-10), within the death-inducing signalling complex. In so-called type 1 cells, proteolytic activation of effector caspases (-3 and -7) by caspase-8 suffices for efficient apoptosis induction. In so-called type 2 cells, however, killing requires amplification of the caspase cascade. This can be achieved through caspase-8-mediated proteolytic activation of the pro-apoptotic Bcl-2 homology domain (BH)3-only protein BH3-interacting domain death agonist (Bid), which then causes mitochondrial outer membrane permeabilisation. This in turn leads to mitochondrial release of apoptogenic proteins, such as cytochrome c and, pertinent for Fas death receptor (DR)-induced apoptosis, Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low Pi), an antagonist of X-linked inhibitor of apoptosis (XIAP), which imposes a brake on effector caspases. In this review, written in honour of Juerg Tschopp who contributed so much to research on cell death and immunology, we discuss the functions of Bid and XIAP in the control of Fas DR-induced apoptosis signalling, and we speculate on how this knowledge could be exploited to develop novel regimes for treatment of cancer. (FasL) can induce apoptosis by a mechanism involving the adaptor protein FADD (Fas-associating protein with a novel death domain) and the proximal initiator caspase, caspase-8 (and in humans also caspase-10). Apoptosis can only be triggered by the membrane-bound form of FasL. Caspase-8 can activate the Bcl-2 homology (BH)3-only protein BH3-interacting domain death agonist (Bid), enabling a crosstalk to the intrinsic apoptotic pathway. Whereas FasL-stimulated type I cells can die independently of the intrinsic apoptotic machinery, type II cells depend on this crosstalk to mitochondria. X-linked inhibitor of apoptosis (XIAP) directly inhibits effector caspases and constitutes a discriminator between the type I and the type II Fas-induced apoptosis signalling. Besides apoptosis, Fas can trigger several non-apoptotic signalling pathways, including RIP1 kinase-dependent cell death (necroptosis), when caspase-8 is missing or disabled, as well as pathways that promote cell activation and cell proliferation. Open QuestionsHow is Fas-induced necroptosis and proliferation regulated at the molecular level? What is the role of XIAP's RING domain in Fas signalling? Why are certain Fas-expressing cell types refractory to FasL-induced killing? What are the roles of soluble FasL?The Death Receptor Fas Fas (also called CD95 or APO-1) is a member of the tumour necrosis factor receptor (TNF-R) superfamily, which also includes receptors for TNFa, TRAIL (TNF-related apoptosisinducing ligand), r...

show abstract

Section: The Death Receptor Fasmentioning

confidence: 99%

Fas death receptor signalling: roles of Bid and XIAP

2011

View full text Add to dashboard Cite

show abstract

“…18 Conversely, stronger stimulation with a hexameric form of sFasL could also engage more Fas leading to a more potent activation of caspases, which kills hepatocytes without the need for Bid. 19 Taken together, these studies indicate that Fas-mediated apoptosis in type II cells is subjected to strong inhibition mediated by XIAP, which could be overcome by Bid-mediated mitochondrial release of Smac, or by stronger stimulations at the receptor level via increased ligand–receptor interactions.…”

Section: Role Of Bid In Cell Death and Liver Injurymentioning

confidence: 83%

Rejuvenating Bi(d)ology

2012

View full text Add to dashboard Cite

The BH3-only Bid protein is a critical sentinel of cellular stress in the liver and the hematopoietic system. Bid's initial `claim to fame' came from its ability—as a caspase-truncated product—to trigger the mitochondrial apoptotic program following death receptor activation. Today we know that Bid can response to multiple types of proteases, which are activated under different conditions such as T-cell activation, ischemical reperfusion injury and lysosomal injury. Activation of the mitochondrial apoptotic program by Bid—via its recently identified receptor mitochondrial carrier homolog 2—involves multiple mechanisms, including release of cytochrome c and second mitochondria-derived activator of caspase (Smac), alteration of mitochondrial cristae organization, generation of reactive oxygen species and engagement of the permeability transition pore. Bid is also emerging—in its full-length form—as a pivotal sentinel of DNA damage in the bone marrow regulated by the ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and Rad3-related (ATR) kinases. The ATM/ATR-Bid pathway is critically involved in preserving the quiescence and survival of hematopoietic stem cells both in the absence and presence of external stress, and a large part of this review will be dedicated to recent advances in this area of research.

show abstract

“…GSE72454). Differences in oligomerization of the DISK components downstream of Jo2 vs. CD95L may determine the overall apoptotic effect (16).…”

Section: Significancementioning

confidence: 99%

Balance between short and long isoforms of cFLIP regulates Fas-mediated apoptosis in vivo

Ram

Ilyukha

Volkova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

cFLIP, an inhibitor of apoptosis, is a crucial regulator of cellular death by apoptosis and necroptosis; its importance in development is exemplified by the embryonic lethality in cFLIP-deficient animals. A homolog of caspase 8 (CASP8), cFLIP exists in two main isoforms: cFLIP L (long) and cFLIP R (short). Although both splice variants regulate death receptor (DR)-induced apoptosis by CASP8, the specific role of each isoform is poorly understood. Here, we report a previously unidentified model of resistance to Fas receptor-mediated liver failure in the wild-derived MSM strain, compared with susceptibility in C57BL/6 (B6) mice. Linkage analysis in F2 intercross (B6 x MSM) progeny identified several MSM loci controlling resistance to Fas-mediated death, including the caspase 8-and FADD-like apoptosis regulator (Cflar) locus encoding cFLIP. Furthermore, we identified a 21-bp insertion in the 3′ UTR of the fifth exon of Cflar in MSM that influences differential splicing of cFLIP mRNA. Intriguingly, we observed that MSM liver cells predominantly express the FLIP L variant, in contrast to B6 liver cells, which have higher levels of cFLIP R. In keeping with this finding, genome-wide RNA sequencing revealed a relative abundance of FLIP L transcripts in MSM hepatocytes whereas B6 liver cells had significantly more FLIP R mRNA. Importantly, we show that, in the MSM liver, CASP8 is present exclusively as its cleaved p43 product, bound to cFLIP L . Because of partial enzymatic activity of the heterodimer, it might prevent necroptosis. On the other hand, it prevents cleavage of CASP8 to p10/20 necessary for cleavage of caspase 3 and, thus, apoptosis induction. Therefore, MSM hepatocytes are predisposed for protection from DR-mediated cell death.T he Fas receptor [also called cluster of differentiation 95 (CD95), APO-1, or TNFRSF6] is a death receptor family member constitutively expressed by most tissues, including the liver (1), where ligation of ubiquitously expressed CD95 leads to potentially lethal hepatitis and liver failure. Although CD95L (Fas ligand) is the only known physiological ligand of CD95 (2), the agonistic antibody Jo2 has been used extensively to ligate CD95 and model CD95-mediated hepatotoxicity and mortality in mice (3). In contrast to the ability of tumor necrosis factor receptor (TNFR)-mediated signaling to lead to profound inflammatory responses in addition to cell death (4), CD95 is predominantly used in apoptosis and necrosis and therefore engages a limited number of downstream components (5). Specifically, ligand binding induces CD95 oligomerization and binding of Fas-associated death domain (FADD) via its death domain (DD), which then recruits caspase 8 (CASP8) via a death effector domain (DED), forming the death-inducing signaling complex (DISK) comprising receptor interacting protein kinase 1 (RIP1), FADD, and CASP8 (6).Interactions of caspase 8 (CASP8) with its enzymatically inactive homolog cFLIP L further complicate the regulation of CD95-mediated signaling (7): CASP8 forms partially enzymatic...

show abstract

The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers #

Cited by 38 publications

References 37 publications

Fas death receptor signalling: roles of Bid and XIAP

Fas death receptor signalling: roles of Bid and XIAP

Rejuvenating Bi(d)ology

Balance between short and long isoforms of cFLIP regulates Fas-mediated apoptosis in vivo

Contact Info

Product

Resources

About