Fas

8 Pages·2000·0.174 MB·English

by  Nagata S.

Fas
Shigekazu Nagata*
Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
*correspondingauthortel:81-6-6879-3310,fax:[phone],e-mail:[email protected]
DOI: 10.1006/rwcy.2000.16004.
SUMMARY cross-hybridization with human cDNA (Watanabe-
Fukunaga et al., 1992b).
Fas is a type I membrane protein belonging to the
TNF/NGF receptor family, and is expressed in vari- Alternative names
oustissuesandcelllines.BindingofFasLoragonistic
anti-Fas antibody to Fas causes apoptosis in Fas- CD95, Apo1.
bearingcells.Thatis,theFasengagementrecruitspro-
caspase8throughanadaptermoleculecalledFADD.
Structure
Oligomerization of pro-caspase 8 induces processing
of pro-caspase 8 to active forms. The caspase 8 then
activates other caspases in the downstream of the Human Fas is a type I membrane protein with
caspase cascade. These caspases then cleave various apparentmolecular mass of 48kDa(Itoh et al., 1991;
cellular substrates to cause morphological changes of Oehm et al., 1992).
the cells, and to degrade chromosomal DNA. The
Fas-mediated apoptosis is involved to kill the acti- Main activities and
vated T cells and B cells, thus downregulating the
pathophysiological roles
immune reaction. The loss-of-function mutations in
Fas in human and mouse cause lymphoproliferation,
and accelerate autoimmune diseases. Fas transduces an apoptotic signal into cells upon
engagement by Fas ligand (FasL) or agonistic anti-
Fas antibody (Itoh et al., 1991; Oehm et al., 1992;
Nagata and Golstein, 1995; Nagata, 1997).
BACKGROUND
Discovery
GENE
Fas was discovered as a cell surface antigen that can Accession numbers
be recognized by a cytotoxic monoclonal antibody
(anti-Fas or anti-Apo1 antibody) against human cell-
Human Fas: M67454 (Itoh et al., 1991).
surface protein (Trauth et al., 1989; Yonehara et al.,
Mouse Fas: M83649 (Watanabe-Fukunaga et al.,
1989). The human Fas cDNA was identified from
1992b).
human leukemia cell line by expression cloning using
the anti-Fas antibody (Itoh et al., 1991), or by using
Sequence
the amino acid sequence information of the purified
protein(Oehmetal.,1992).ThemouseFascDNAwas
subsequently isolated from mouse cDNA library by See Figure 1.
1650 Shigekazu Nagata
Figure 1 Nucleotide sequence for human Fas.
1 CACGCTTCTG GGGAGTGAGG GAAGCGGTTT ACGAGTGACT TGGCTGGAGC CTCAGGGGCG
61 GGCACTGGCA CGGAACACAC CCTGAGGCCA CCCCTTGCTG CCCAGGCGGA GCTGCCTCTT
121 CTCCCGCGGG TTGGTGGACC CGCTCACTAC GGAGTTCGGG AAGCTCTTTC ACTTCCCACC
181 ATTGCTCAAC AACCATGCTG GGCATCTGGA CCCTCCTACC TCTGGTTCTT ACGTCTGTTG
241 CTAGATTATC GTCCAAAAGT GTTAATGCCC AAGTGACTGA CATCAACTCC AAGGGATTGG
301 AATTGAGGAA GACTGTTACT ACAGTTGAGA CTCAGAACTT GGAAGGCCTG CATCATGATG
361 GCCAATTCTG CCATAAGCCC TGTCCTCCAG GTGAAAGGAA ACCTAGGGAC TGCACAGTCA
421 ATGGGGATGA ACCAGACTGC GTGCCCTGCC AAGAAGGGAA GGAGTACACA GACAAAGCCC
481 ATTTTTCTTC CAAATGCAGA AGATGTAGAT TGTGTGATGA AGGACATGGC TTAGAAGTGG
541 AAATAAACTG CACCCGGACC CAGAATACCA AGTGCAGATG TAAACCAAAC TTTTTTTGTA
601 ACTCTACTGT ATGTGAACAC TGTGACCCTT GCACCAAATG TGAACATGGA ATCATCAAGG
661 AATGCACACT CACCAGCAAC ACCAAGTGCA AAGAGGAAGG ATCCAGATCT AACTTGGGGT
721 GGCTTTGTCT TCTTCTTTTG CCAATTCCAC TAATTGTTTG GGTGAAGAGA AAGGAAGTAC
781 AGAAAACATG CAGAAAGCAC AGAAAGGAAA ACCAAGGTTC TCATGAATCT CCAACCTTAA
841 ATCCTGAAAC AGTGGCAATA AATTTATCTG ATGTTGACTT GAGTAAATAT ATCACCACTA
901 TTCCTGGAGT CATGACACTA AGTCAAGTTA AAGGCTTTGT TCGAAAGAAT GGTGTCAATG
961 AAGCCAAAAT AGATGAGATC AAGAATGACA ATGTCCAAGA CACAGCAGAA CAGAAAGTTC
1021 AACTGCTTCG TAATTGGCAT CAACTTCATG GAAAGAAAGA AGCGTATGAC ACATTGATTA
1081 AAGATCTCAA AAAAGCCAAT CTTTGTACTC TTGCAGAGAA AATTCAGACT ATCATCCTCA
1141 AGGACATTAC TAGTGACTCA GAAAATTCAA ACTTCAGAAA TGAAATCCAA AGCTTGGTCT
1201 AGAGTGAAAA ACAACAAATT CAGTTCTGAG TATATGCAAT TAGTGTTTGA AAAGATTCTT
1261 AATAGCTGGC TGTAAATACT GCTTGGTTTT TTACTGGGTA CATTTTATCA TTTATTAGCG
1321 CTGAAGAGCC AACATATTTG TAGATTTTTA ATATCTCATG ATTCTGCCTC CAAGGATGTT
1381 TAAAATCTAG TTGGGAAAAC AAACTTCATC AAGAGTAAAT GCAGTGGCAT GCTAAGTACC
1441 CAAATAGGAG TGTATGCAGA GGATGAAAGA TTAAGATTAT GCTCTGGCAT CTAACATATG
1501 ATTCTGTAGT ATGAATGTAA TCAGTGTATG TTAGTACAAA TGTCTATCCA CAGGCTAACC
1561 CCACTCTATG AATCAATAGA AGAAGCTATG ACCTTTTGCT GAAATATCAG TTACTGAACA
1621 GGCAGGCCAC TTTGCCTCTA AATTACCTCT GATAATTCTA GAGATTTTAC CATATTTCTA
1681 AACTTTGTTT ATAACTCTGA GAAGATCATA TTTATGTAAA GTATATGTAT TTGAGTGCAG
1741 AATTTAAATA AGGCTCTACC TCAAAGACCT TTGCACAGTT TATTGGTGTC ATATTATACA
1801 ATATTTCAAT TGTGAATTCA CATAGAAAAC ATTAAATTAT AATGTTTGAC TATTATATAT
1861 GTGTATGCAT TTTACTGGCT CAAAACTACC TACTTCTTTC TCAGGCATCA AAAGCATTTT
1921 GAGCAGGAGA GTATTACTAG AGCTTTGCCA CCTCTCCATT TTTGCCTTGG TGCTCATCTT
1981 AATGGCCTAA TGCACCCCCA AACATGGAAA TATCACCAAA AAATACTTAA TAGTCCACCA
2041 AAAGGCAAGA CTGCCCTTAG AAATTCTAGC CTGGTTTGGA GATACTAACT GCTCTCAGAG
2101 AAAGTAGCTT TGTGACATGT CATGAACCCA TGTTTGCAAT CAAAGATGAT AAAATAGATT
2161 CTTATTTTTC CCCCACCCCC GAAAATGTTC AATAATGTCC CATGTAAAAC CTGCTACAAA
2221 TGGCAGCTTA TACATAGCAA TGGTAAAATC ATCATCTGGA TTTAGGAATT GCTCTTGTCA
2261 TACCCTCAAG TTTCTAAGAT TTAAGATTCT CCTTACTACT ATCCTACGTT TAAATATCTT
2341 TGAAAGTTTG TATTAAATGT GAATTTTAAG AAATAATATT TATATTTCTG TAAATGTAAA
2401 CTGTGAAGAT AGTTATAAAC TGAAGCAGAT ACCTGGAACC ACCTAAAGAA CTTCCATTTA
2461 TGGAGGATTT TTTTGCCCCT TGTGTTTGGA ATTATAAAAT ATAGGTAAAA GTACGTAATT
2521 AAATAATGTT TTTG
Chromosome location and linkages (Itoh et al., 1991; Oehm et al., 1992). A single trans-
membrane domain of 17 amino acids divides the
molecule into the extracellular region of 157 amino
Human chromosome 10q24.1 (Inazawa et al., 1992)
acids,andthecytoplasmicregionof145aminoacids.
Mouse chromosome 11 (Watanabe-Fukunaga et al.,
The extracellular region can be further divided into
1992b) linked to lpr mutation.
three cysteine-rich subregions.
Relevant homologies and species
PROTEIN
differences
Accession numbers
The extracellular region of Fas has a homology (25–
HumanFas:PIDg105364,g182410(Itohetal.,1991) 30% homology) with that of other TNF/NGF
Mouse Fas: PID g346698, g193226 (Watanabe- receptor family members (Itoh et al., 1991; Oehm
Fukunaga et al., 1992b). et al., 1992; Smith et al., 1994). The cytoplasmic
region of Fas contains a domain of about 80 amino
acids that shows a homology with the corresponding
Description of protein
region of the TNF type I receptor (Itoh and Nagata,
1993; Tartaglia et al., 1993) and the death receptors
Human Fas is comprised of 319 amino acids with a DR3 and DR4 (Ashkenazi and Dixit, 1998). The
signal sequence of 15 amino acids at the N-terminus domain is called the ‘death domain’. The amino acid
Fas 1651
sequence of mouse Fas hasan identity of 49.3% with SIGNAL TRANSDUCTION
human Fas (Watanabe-Fukunaga et al., 1992b).
There is no species-specificity among human,
Associated or intrinsic kinases
mouse, and rat (Takahashi et al., 1994).
The cytoplasmic region of Fas and its signaling
molecule, FADD, is constitutively phosphorylated
Affinity for ligand(s)
(Kennedy and Budd, 1998). Several kinases including
RIP (receptor-interacting protein) and p59fyn were
Fas ligand binds to Fas with a K of about 1.0nM. reportedtointeractwiththecytoplasmicregionofthe
d
Fas receptor (Stanger et al., 1995; Atkinson et al.,
1996). However, the cells deficient in RIP kinase are
Cell types and tissues expressing potent to transduce the apoptotic signal, suggesting
that RIP is not essential for the Fas-mediated
the receptor
apoptotic signal transduction (Ting et al., 1996).
Fas is ubiquitously expressed in various tissues and
cells (Watanabe-Fukunaga et al., 1992b; Leitha¨user Cytoplasmic signaling cascades
et al., 1993). In particular, Fas is expressed in the
thymus, activated T cells, hepatocytes, and heart.
Acascadeofcaspases(cysteineproteases)isactivated
LymphomasofT cell and B cell originexpress ahigh
by Fas engagement (Enari et al., 1996; Nagata, 1997;
level of Fas, constitutively (Falk et al., 1992; Debatin
Tewari and Dixit, 1995) (Figure 2). Binding of Fas
et al., 1994).
ligand or agonisticanti-Fas antibodytoFasactivates
Fas.Fasligandisatrimer,andtheagonisticanti-Fas
antibodies are IgM (immunoglobulin pentamer), or
Regulation of receptor expression IgG3thattendstoaggregate.TheF(ab0) fragmentof
2
anti-Apo1 antibody or other isotypes does not
Expression of Fas in mature T cells is upregulated by activate Fas (Dhein et al., 1992), suggesting that Fas
activation with phorbol myristate acetate and must be trimerized or aggregated to the higher order
ionomycin. A cis-regulatory element of NF(cid:20)B at to transduce the signal (Takahashi et al., 1996). Tri-
positions (cid:255)295 to (cid:255)286 in the 50 flanking region of merization of Fas by FasL or agonistic anti-Fas or
human Fas chromosomal gene is responsible for the Apo1antibodycausesrecruitmentofcaspase8toFas
induced expression of Fas in T cells (Chan et al., throughanadaptercalledFADD(Boldinetal.,1995,
1999). Oncogene p53 upregulates the expression 1996; Chinnaiyan et al., 1995; Muzio et al., 1996).
of Fas (Owen-Schaub et al., 1995). p53-responsive This activatescaspase8,which thensequentiallyacti-
elements in the intron 1 and 50 promoter flanking vatesothercaspasessuchascaspases3,6,and7inthe
region of human Fas gene seem to be responsible for downstream of the caspase cascade (Hirata et al.,
the p53-dependent expression of Fas (Muller et al., 1998;Kawaharaetal.,1998).Caspasesthusactivated
1999). would cleave various cellular substrates to progress
the apoptotic program (Martin and Green, 1995;
Nagata, 1997). One of the caspase substrates is
ICAD (inhibitor of caspase-activated DNase)/DFF-
Release of soluble receptors
45 (DNA fragmentation factor 45) (Liu et al., 1997;
Sakahira et al., 1998). The cleavage of ICAD by
The soluble Fas can be produced by alternative caspase 3 leads to the activation of a DNase (CAD),
splicing (Cascino et al., 1995; Hughes and Crispe, which causes the DNA fragmentation seen in most
1995; Papoff et al., 1996). Patients with nonhemato- apoptotic cells (Enari et al., 1998). This signal
poietic malignancies or ATL (adult T cell leukemia) transduction cascade was confirmed by knocking-
have a high level of soluble Fas in the serum out the respective signaling molecules. That is, the
(Sugawara et al., 1997). There is a soluble decoy cells lacking FADD or caspase 8 do not undergo
receptor(DcR3)towhichFasLbindswithanaffinity apoptosis induced by Fas activation (Varfolomeev
similar to that with which it binds the authentic Fas etal.,1998;Yehetal.,1998;Zhangetal.,1998a).The
receptor (Pitti et al., 1999). The DcR3 gene is ampli- cells lacking caspase 3 or ICAD do not show DNA
fied in about half of human lung cancer and colon fragmentation induced by Fas activation (Woo et al.,
cancer cells. 1998; Zhang et al., 1998b).
1652 Shigekazu Nagata
Figure2 Fas-inducedapoptosis.BindingofFasligand DOWNSTREAM GENE
to Fas induces trimerization of Fas, which recruits pro-
ACTIVATION
caspases 8 via an adapter called FADD/MORT1, and
induces its processing to the mature form. In one
signalingpathway,caspase8directlyactivatescaspase3 Transcription factors activated
downstreamofthecaspasecascade.Inanotherpathway,
caspase8cleavesBid,aproapoptoticmemberoftheBcl-
Transcription factors are not activated by Fas
2 family. The cleaved Bid then enters mitochondria to
engagement, although NF(cid:20)B was reported to be
causereleaseofcytochromeC,whichactivatescaspase9
together with Apaf-1. The caspase 9 then activates activated in some cell lines (Rensing et al., 1995).
caspase 3. Caspase 3, thus activated, cleaves various
cellular substrates to induce morphological changes of
cells and nuclei. One of the caspase 3 substrates is Genes induced
ICAD/DFF-45, which is complexed with CAD, a spe-
cific DNase. Cleavage of ICAD by caspase 3 releases
The Fas activation quickly leads to cleavage of
CADfromICAD,andCADthenentersnucleitocause
chromosomal DNA (Itoh et al., 1991), and does not
DNA fragmentation.
induce gene expression.
BIOLOGICAL CONSEQUENCES
OF ACTIVATING OR INHIBITING
RECEPTOR AND
PATHOPHYSIOLOGY
Unique biological effects of
activating the receptors
Activation of Fas causes apoptotic cell death in most
cases (Nagata, 1997). It may also cause necrotic cell
death in certain conditions (Vercammen et al., 1998).
Phenotypes of receptor knockouts
and receptor overexpression mice
Mouse mutation lpr (lymphoproliferation) is a loss-
of-function mutation of Fas (Watanabe-Fukunaga
et al., 1992a) (Figure 3). In one allele (lpr), an early
transposable element (ETn) is inserted in intron 2 of
Many other signaling cascades initiated by the the Fas chromosomal gene (Adachi et al., 1993). The
activated Fas leading to apoptosis have been pro- Fas transcript prematurely terminates in intron 2.
posed. For example, ceramide was postulated to However,theinhibitionofexpressionisnotcomplete,
mediate the Fas signal by activating the Ras/MAP as demonstrated by the presence of full-length Fas
kinase pathway (Cifone et al., 1994; Gulbin et al., mRNA, albeit at a low level, suggesting that lpr is a
1995; Tepper et al., 1995). However, recent analysis leaky mutation. In the other allele (lprcg), a point
suggests that ceramide is not activated during Fas- mutation that causes replacement of an amino acid
mediated apoptosis, and ceramide is probably not from isoleucine to asparagine is introduced in the
involved in this signaling pathway (Hofmann and death domain of the Fas cytoplasmic region, which
Dixit, 1998; Hsu et al., 1998; Watts et al., 1997). abolishestheabilityofFastotransducetheapoptotic
Other pathwaysproposed involvingDAXX, JNK, or signal (Watanabe-Fukunaga et al., 1992a). Mice
Bid (Brenner et al., 1997; Yang et al., 1997; Li et al., carrying the lpr mutation develop lymphadenopathy
1998; Luo et al., 1998) also need to be confirmed. andsplenomegaly,produceautoantibodies,andsuffer
Fas 1653
Figure 3 Mutations of Fas in lpr-mice and in human patients with Canale–Smith syndrome. (a) A
mutationintheFasgeneinlprmice.ThestructureofmouseFaschromosomalgeneisschematically
shown. In lpr mice an early transposable element (ETn) carrying poly(A) addition signal on a long
terminal repeat (LTR) is inserted in intron 2 of the gene. This causes premature termination of Fas
transcript.(b)PointmutationsintheFasdeathdomaininhumanCanale–Smithsyndromeandlprcg
mice. The amino acid sequences of the death domain of human and mouse Fas are aligned. The
aminoacidreplacementsinpatientsofCanale–Smithsyndromeareindicatedontheupperline,while
the mutation in lprcg mice is shown in the lower line.
wild
lpr
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