7/31/2019 New twists in the unfolded protein response

1/4

`lje`/`lje`}mj`om`}/ktb

Mtk}} coh Tko/ Lje` 4134>39`1148=/ HKJ9 31/2008+`Lje`/1148= 3 ke 8

Jo `pnctzkxjm m`ll} gcoz qtkx`jo} ct` }zoxf`}j}`h

jo xf` `ohkqlc}gjm t`xjmplpg &@T*, coh rjxfjo

`cmf m`ll xfj} qtkhpmxjko qtkm`}} gp}x d` mct`'

pllz }zomftkoj}`h rjxf }`mt`xjko coh xf` `vqktx

k qtkx`jo} tkg xf` @T/ Coz cjlpt` xk gcjoxcjo c

dclcom` d`xr``o xf` qtkhpmxjko k qtkx`jo}

rfjmf jouklu`} }xtjob} k cgjok cmjh} klhjob joxk

}q`mjm }fcq`}coh xf`jt h`qctxpt` tkg xf` @T

rjll l`ch xk `ttkt} jo xf` }zoxf`}j} qtkm`}} coh,

`u`oxpcllz, xk xkvjmjxz xftkpbf c qf`okg`oko

nokro c} @T }xt`}}/ Xf` mkll`mxjko k g`mfc'

oj}g} xfcx m`ll} p}` xk mkgdcx @T }xt`}} j} nokro

c} xf` poklh`h qtkx`jo t`}qko}`/ Rtjxjob jo`Lj`, Qfjljqq Njggjb, Gctmz Hjcy coh mk'rktn`t}

cx xf` Poju`t}jxz k Mcljktojc cx ]co Etcomj}mk

&PM]E* t`qktx xf` t`}plx} k `vq`tjg`ox} ko

]mfjyk}cmmfctkgzm`} qkgd`, c }}jko z`c}x, xfcx

t`u`cl c}q`mx} k xf` poklh`h qtkx`jo t`}qko}`

xfcx fcu` okx d``o kd}`tu`h d`kt` &Njggjb

`x cl/, 4134*/

Jo cll }z}x`g} }xphj`h xk hcx`, m`ll} t`}qkoh xk

co cmmpgplcxjko k gj}klh`h qtkx`jo} jo xf` @T

dz qtkhpmjob gkt` qtkx`jo'klhjob gcmfjo`tz

rjxfjo xf` @T/ Xfj} qtkm`}} j} jojxjcx`h dz c }xt`}}

xtco}hpm`t`jxf`t JT@3, Q@TN kt CXE5xfcx }qco}

xf` g`gdtco` d`xr``o xf` @T coh xf` t`}x k

xf` m`ll &Rclx`t coh Tko, 4133*/ JT@3, rfjmf j}

mko}`tu`h jo cll `pnctzkx`}, j} c hpcl'pomxjko

`oyzg` xfcx h`x`mx} poklh`h qtkx`jo} jo xf` @T

coh xf`o }`oh} }jbocl} xk xf` opml`p} k xf` m`l

xk chht`}} xfj} qtkdl`g/

Jo g`xcykco}, qlcox} coh dphhjob z`c}x, xfj}

}jboclljob jouklu`} xf` JT@3 t`gkujob c }fktx

tcbg`ox tkg rjxfjo c }xtcoh k g`}}`ob`t TOC

&gTOC*c qtkm`}} nokro c} gTOC }qljmjob

Xfj} }fktx tcbg`ox j} h`btch`h coh xf` xrk

econjob qj`m`} k gTOC ct` ikjo`h xkb`xf`t xk

`omkh` co cmxju` xtco}mtjqxjko cmxkt xfcx }q`mj

mcllz jomt`c}`} xf` vqt`}}jko k xf` qtkx`jo} xfc

gcn` pq xf` qtkx`jo'klhjob gcmfjo`tz kpoh jo

xf` @T/ Poxjl t`m`oxlz jx rc} b`o`tcllz cbt``h xfc

xf` qtjgctz pomxjko k JT@3 hptjob @T }xt`}}

jouklu`h xfj} xtco}mtjqxjkocl cmxjucxjko, coh jx rc}

cl}k xfkpbfx xfcx xfj} qtkm`}} t`spjt`h c }q`mjm

gTOC }pd}xtcx` &VDQ3 kt g`xcykco}, dYJQ51 k

qlcox}, coh FCM3 kt dphhjob z`c}x*/ Ej}}jko

z`c}x rc} nokro xk d` co `vm`qxjko xk xfj}cqq`cljob pojxz d`mcp}` ok coclkbkp} JT@3 }pd'

}xtcx` fch `u`t d``o jh`oxj`h &Ejbpt` 3C*/

Jo 4115 jx rc} hj}mku`t`h xfcx @T }xt`}} jo htk'

}kqfjlc m`ll} l`ch} xk xf` h`mcz k c opgd`t k

@T'lkmclj}`h gTOC} &Fkllj`o coh R`j}}gco

4115*, coh }jom` xf`o jx fc} d`mkg` cqqct`ox

xfcx ml`cucb` k xf` gTOC} dz JT@3 j} xf`

t}x }x`q, coh cl}k xf` ljgjxjob }x`q, jo xf`j

h`btchcxjko/ Xfj} qtkm`}}, lcx`t x`tg`h t`bplcx`h

Mkqztjbfx Mtk}} coh Tko/ Xfj}

ctxjml` j} hj}xtjdpx`h poh`t xf` x`tg} k

xf` Mt`cxju` Mkggko} Cxxtjdpxjko

Ljm`o}`, rfjmf q`tgjx} pot`}xtjmx`h p}`

coh t`hj}xtjdpxjko qtkujh`h xfcx xf`

ktjbjocl cpxfkt coh }kptm` ct` mt`hjx`h/

JO]JBFX

M@LL DJKLKBZ

O`r xrj}x} jo xf` poklh`hqtkx`jo t`}qko}`Xf` t`}qko}` k]/ qkgd`, cl}k nokro c} e}}jko z`c}x, xk gj}klh`h

qtkx`jo} jouklu`} g`mfcoj}g} xfcx fcu` okx d``o kd}`tu`h jo kxf`t

}q`mj`}/

D@O@HJMX M ] MTK]] COH HCUJH TKO

T`lcx`h t`}`ctmf ctxjml` Njggjb Q, Hjcy G,

Yf`ob I, Rjlljcg} M, Lcob C, Ctcbo X, Lj F,

Rclx`t Q/ 4134/ Xf` poklh`h qtkx`jo t`}qko}`

jo e}}jko z`c}x gkhplcx`} }xcdjljxz k }`l`mx

gTOC} xk gcjoxcjo qtkx`jo fkg`k}xc}j}/

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Jgcb` Ml`cucb` k gTOC} dz xf`

qtkx`jo'klhjob }`o}kt JT@3

http://elife.elifesciences.org/http://dx.doi.org/10.7554/elife.00243http://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/http://dx.doi.org/10.7554/elife.00048http://dx.doi.org/10.7554/elife.00048http://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/http://dx.doi.org/10.7554/elife.00243http://creativecommons.org/licenses/by/3.0/http://www.elifesciences.org/the-journal/open-access/http://elife.elifesciences.org/

7/31/2019 New twists in the unfolded protein response

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M`ll djklkbz | O`r xrj}x} jo xf` poeklh`h qtkx`jo t`}qko}

Mtk}} coh Tko/ Lje` 4134>39`1148=/ HKJ9 31/2008+`Lje`/1148= 4 ke 8

Jo}jbfx

Poeklh`h qtkx`jo}

;;;

@vk}kg`Ml`cucb` keDJQ3 gTOCxtco}mtjqx

H`mcz ke gTOC h`}xjo`hekt xf` @T

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Ejbpt` 3/ Xf` poklh`h qtkx`jo t`}qko}` jo ]/ qkgd` coh kxf`t }q`mj`}/ &C* Xf` cmmpgplcxjko poklh`h qtkx`jo} jo

xf` ohkqlc}gjm t`xjmplpg &@T* k]/ qkgd` l`ch} xk cmxjucxjko k JT@3 &qt`}pgcdlz dz opml`kxjh` djohjob &bt``o*,

cpxk'qfk}qfktzlcxjko &t`h* coh xf` ktgcxjko k hjg`t}*, rfjmf j} xpto l`ch} xk xf` ml`cucb` k gTOC} jo xf`

mzxk}kl/ Xf` }pd}`sp`ox h`btchcxjko k xf` ml`cu`h gTOC} &nokro c} TJHH* coh `vqlp}jko tkg xf` m`ll &ujc xf`

`vk}kg`* t`hpm`h xf` qtkx`jo'klhjob lkch ko xf` @T/ Fkr`u`t, c} h`}mtjd`h jo xf` x`vx, xf` gTOC xfcx omkh`}

kt xf` gkl`mplct mfcq`tko` Djq3 `}mcq`} xfj} cx`9 clxfkpbf jx j} ml`cu`h cx xf` = poxtco}lcx`h t`bjko &}fkro dz xf`

c}x`tj}n*, xf` 0 Djq3 gTOC tcbg`ox j} et}x }xcdjljy`h coh xf`o xtco}lcx`h joxk Djq3 dz xf` tjdk}kg`/ Xf` `ofcom`h

qtkhpmxjko kDjq3 f`lq} xk jomt`c}` xf` qtkx`jo'klhjob mcqcmjxz k xf` @T/ Xf` }cg` JT@3 hjg`t mco q`tktg dkxf

Djq3 gTOC ml`cucb` coh TJHH9 fkr`u`t, lctb`t JT@3 kljbkg`t} &tjbfx* mco cl}k q`tktg TJHH jo c }`mkoh l`u`l k

xf` poklh`h qtkx`jo t`}qko}`/ &D* Com`}xtcl JT@3 gcz fcu` qk}}`}}`h TJHH cmxjujxz qtjkt xk xf` `uklpxjko k xf`

z`c}x} &xkq*, cojgcl} &gjhhl`* coh qlcox} &dkxxkg*/ Xfj} u`}xjbjcl TJHH pomxjko j} okx `ujh`ox jo dphhjob z`c}x

&]/ m`t`uj}jc`*, coh jx j} okx nokro j jx `vj}x} jo qlcox} &Ctcdjhkq}j}*, dpx jx j} `ujh`ox jo xf` cojgcl} &g`xcykco}*/

Fkr`u`t, jo cll xft`` mc}`} JT@3 v`tx} xtco}mtjqxjkocl mkoxtkl dz }qljmjob gTOC xk t`bplcx` xf` vqt`}}jko k

uctjkp} xtco}mtjqxjko cmxkt} &FCM3, VDQ3 coh dYJQ51*/ Xf` poklh`h qtkx`jo t`}qko}` jo p}jko z`c}x &]/ Qkgd`* j}

hj t`ox jo xfcx jx jouklu`} TJHH coh xf` hjt mx qk}x'xtco}mtjqxjkocl }xcdjlj}cxjko k xf` gkl`mplct mfcq`tko` Djq3/

TOc}` L j} c hj}xcox t`lcxju` k JT@3 xfcx xtjbb`t} gTOC h`mcz jo gcggcl} jo c rcz xfcx j} okx hj}}jgjlct xk TJHH/

JT@3'h`q`oh`ox h`mcz, fc} cl}k d``o kpoh jo

gcggcljco m`ll} coh j} xfkpbfx xk t`hpm` xf`

qtkx`jo'klhjob lkch dz qtkgqxjob xf` qt`'`gqxju`

h`btchcxjko k gTOC} xfcx ct` h`}xjo`h kt xf`

@T &Fkllj`o `x cl/, 411:*/ Xfj} ohjob, rfjmf

mcg` c} c }ptqtj}` cx xf` xjg`, }`x xf` }m`o` kt

xf` lcx`}x rktn ko xf` poklh`h qtkx`jo t`}qko}`

jo }}jko z`c}x/

Njggjb coh mk'rktn`t}, rktnjob jo Q`x`

Rclx`t} lcd cx PM]E, mkohpmx`h c xtco}mtjqx cocl'

z}j} k @T'}xt`}}`h ]/ qkgd` m`ll} coh kpoh c

hj}xjomx h`mt`c}` jo xf` cdpohcom` k gTOC}

http://dx.doi.org/10.7554/elife.00243http://dx.doi.org/10.7554/elife.00243

7/31/2019 New twists in the unfolded protein response

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M`ll djklkbz | O`r xrj}x} jo xf` poeklh`h qtkx`jo t`}qko}

Mtk}} coh Tko/ Lje` 4134>39`1148=/ HKJ9 31/2008+`Lje`/1148= = ke 8

Jo}jbfx

`omkhjob kt qtkx`jo} xfcx r`t` h`}xjo`h kt xf` @T

&Njggjb `x cl/, 4134*/ Eptxf`t gkl`mplct coclz}j}

mkotg`h JT@3'h`q`oh`ox ml`cucb` k xfj} }pd}`x

k gTOC}, kllkr`h dz h`btchcxjko k xf` 0 coh

= tcbg`ox}9 xf`}` ct` xf` fcllgctn} k t`bplcx`h

JT@3'h`q`oh`ox h`mcz &TJHH*, coh xf`z }pbb`}x

xfcx xfj} qtkm`}} gjbfx qtkujh` xf` kpohcxjko k

xf` poklh`h qtkx`jo t`}qko}` jo xf`}` m`ll}/

Xf` }jx`} k xf` JT@3'h`q`oh`ox gTOC ml`cu'cb` jo ]/ qkgd` }fct` }kg` }`sp`om` fkgklkbz

rjxf xfk}` k kxf`t }q`mj`}, dpx okx `okpbf xk

cmmkpox `oxjt`lz kt xf` cqqct`ox }q`mjmjxz k

TJHH/ Jo cmx, xf` hjmplxz jo jh`oxjzjob ml`ct

tpl`} kt TJHH jo xfj} }xphz coh kxf`t} fch tcj}`h

c opgd`t k sp`}xjko} cdkpx xf` qf`okg`oko

jx}`l/ J} TJHH c dkoc eh` pomxjkocl kpxqpx k xf`

poklh`h qtkx`jo t`}qko}`; Kt j} jx co jtt`l`ucox

dpx jo`ujxcdl` mktkllctz k c qkx`ox @T'`gd`hh`h

TOc}`; Rfjl}x dphhjob z`c}x cqq`ct xk }ptuju`

rjxfkpx TJHH, xf` PM]E x`cg gcn`} c }xtkob

b`o`xjm mc}` kt jx} jgqktxcom` jo }}jko z`c}x,

`}xjgcxjob xfcx TJHH cmmkpox} kt c 30% h`mt`c}`

jo poklh`h qtkx`jo lkch ko xf` @T k rjlhxzq`

}}jko z`c}x/ Clxfkpbf xfj} j} c gkh`}x h`mt`c}`,

jx j} rktxf okxjob xfcx xf` Q@TN dtcomf k xf`

poklh`h qtkx`jo t`}qko}` jo xf` cmxju` }`mt`xktz

m`ll} k xf` gcggcljco qcomt`c} gcn`} co

jgqktxcox mkoxtjdpxjko xk m`ll }ptujucl, `u`o

xfkpbf jx kolz t`hpm`} xf` poklh`h qtkx`jo lkch

dz co `}xjgcx`h =1% &Fcthjob `x cl/, 4113*/ Jo

mkoxtc}x, mplxpt`h gcggcljco m`ll} mco }ptuju`

cmpx` @T }xt`}} rjxfkpx xf` f`lq k xf` JT@3 xtco'

}mtjqxjkocl dtcomf &Mtk}} `x cl/, 4134*/

Xf`}` o`r ohjob} jo ]/ qkgd` cl}k fjbfljbfxxf` qkx`oxjcl kt }`l`mxju` TJHH xk l`ch xk c spclj'

xcxju` mfcob` jo m`ll qfz}jklkbz, jo chhjxjko xk c

spcoxjxcxju` t`hpmxjko jo xf` poklh`h qtkx`jo

lkch/ Xf` }`l`mxju` h`mcz k xtco}mtjqx} xfcx ct`

jouklu`h jo }x`tkl g`xcdklj}g j} c }clj`ox vcgql`

k xfj}, }jom` }x`tkl cmmpgplcxjko qtkgkx`} @T

}xt`}} jo gcggcljco m`ll} &E`ob `x cl/, 411=* coh

dphhjob z`c}x &Qjo`cp `x cl/, 411:*/

Xf` d`fcujkpt k c qtkx`jo mcll`h Djq3 qtk'

ujh`h co po`vq`mx`h xrj}x jo xf` }xktz k xf`

poklh`h qtkx`jo t`}qko}` k]/ qkgd`/ Djq3 j} c

gkl`mplct mfcq`tko`, c qtkx`jo xfcx f`lq} kxf`t

qtkx`jo} kt gcmtkgkl mpl`} xk klh coh poklh jom`ll}, coh Njggjb, Hjcy coh mk'rktn`t} kpoh xfcx

xf` gTOC xfcx `omkh`} kt Djq3 rc} `l`ucx`h jo

rjlhxzq` @T'}xt`}}`h ]/ qkgd`/ Gk}x }q`mj`}

jomt`c}` xf` `vqt`}}jko k gkl`mplct mfcq`tko`}

dz jomt`c}job xf` tcx` k xtco}mtjqxjko k xf`jt

`omkhjob gTOC/ Xf` t`}`ctmf`t} kpoh xfcx xf`

t`}qko}` jo ]/ qkgd` rc} qk}x'xtco}mtjqxjkocl/

Jo qctxjmplct xf`z kpoh xfcx xf` Djq3 gTOC

rc} ml`cu`h cx c xzqjmcl TJHH }jx` jo xf`

= poxtco}lcx`h t`bjko &johjmcx`h dz co c}x`tj}n jo

Ejbpt` 3C*/ Fkr`u`t, poljn` cll kxf`t nokro

TJHH xctb`x}, rfjmf ct` tcqjhlz h`btch`h kl

lkrjob ml`cucb`, xf` 0 gTOC tcbg`ox xfcx

mkoxcjo} xf` mkhjob }`sp`om` kt xf` Djq3

gkl`mplct mfcq`tko` j} }xcdjlj}`h, rfjmf l`ch} xk

xf` jomt`c}`h qtkhpmxjko kDjq3 coh, xf`t`kt`

xk jomt`c}`h qtkx`jo'klhjob mcqcmjxz jo xf` @T/

Xf` mcxclzxjm t`}jhp`} jo JT@3 ct` r`ll mko'}`tu`h d`xr``o ]/ Qkgd` coh kxf`t }q`mj`}, coh

xf` PM]E t`}plx} }pbb`}x xfcx JT@3 j} hjt`mxlz

t`}qko}jdl` kt xf` ml`cucb` k Djq3 gTOC jo

]/ qkgd`/ Rfjl}x gpmf j} z`x xk d` poh`t}xkkh

cdkpx xf` g`mfcoj}g poh`tlzjob xf` mkpox`t

joxpjxju` }xcdjljycxjko k xf` 0 tcbg`ox, xf`

kpxqpx j} ml`ct coh t`qt`}`ox} c oku`l qk}x'xtco'

}mtjqxjkocl cqqtkcmf xk mkgdcxjob @T }xt`}}/

Xf`}` ohjob} cl}k jllpgjocx` xf` `uklpxjko k

xf` poklh`h qtkx`jo t`}qko}` &Ejbpt` 3D*/ Xf`

mkggko }fct`h djklkbz cqq`ct} xk d` xf`

ml`cucb` coh }qljmjob k TOC dz JT@3, rjxf

xf` djkgkl`mplct cqqctcxp} xfcx mkpql`} xfj}

cmxjujxz xk xf` t`bplcx`h `vqt`}}jko k c xtco'

}mtjqxjko cmxkt `g`tbjob kolz lcx`t/ Jo qlcox}, k

`vcgql`, xfj} }qljmjob h`l`x`} c t`bjko k gTOC

xfcx mkh`} kt c }q`mjm xtco}g`gdtco` }xtpmxpt`

rfjmf ljd`tcx`} c x`xf`t`h xtco}mtjqxjko cmxk

tkg xf` @T &H`ob `x cl/, 4133*/ Jo g`xcykco}

coh dphhjob z`c}x xf` cmxjujxz k JT@3 j} xk

mkoxtkl xf` xtco}lcxjko k co cmxju` xtco}mtjq'

xjko cmxkt/ Coh xf` cqq`ctcom` k TOc}` L, c

hj}xcox t`lcxju` k JT@3 xfcx j} jouklu`h jo

joocx` jggpojxz jo gcggcl} &Gclcxfj `x cl/

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Joh``h, bju`o xf` g`mfcoj}xjm hju`t}jxz kt h`cl

job rjxf poklh`h qtkx`jo} jo xf` @T xfcx j} fjbf

ljbfx`h dz xf` PM]E rktn, xf` }jgjlctjxj`} jo xf`

t`}qko}`} k dphhjob z`c}x &]/ m`t`uj}jc`* coh

xf` g`xcykco} j} spjx` t`gctncdl`/ Jx rjll d`

c}mjocxjob xk hj}mku`t fkr xf` poklh`h qtk

x`jo t`}qko}` fc} `uklu`h jo `cmf ljo`cb`/

D`o`hjmx M ] Mtk}} j} cx xf` Poju`t}jxz k Mcgdtjhb`

G`xcdkljm T`}`ctmf Lcdktcxktj`} coh xf` OJFT

Mcgdtjhb` Djkg`hjmcl T`}`ctmf M`oxt`, Mcgdtjhb`,

Pojx`h Njobhkgdmm==Ag`h}mfl/mcg/cm/pn

Hcujh Tko j} co `Lj` t`uj`rjob `hjxkt, coh j} cx xf`

Poju`t}jxz k Mcgdtjhb` G`xcdkljm T`}`ctmf

Lcdktcxktj`} coh xf` OJFT Mcgdtjhb` Djkg`hjmcl

T`}`ctmf M`oxt`, Mcgdtjhb`, Pojx`h Njobhkg

ht=51Ag`h}mfl/mcg/cm/pn

Mkgq`xjob jox`t`}x}9Xf` cpxfkt} h`mlct` xfcx ok

mkgq`xjob jox`t`}x} `vj}x

Qpdlj}f`h30 Kmxkd`t 4134

http://dx.doi.org/10.7554/elife.00243http://dx.doi.org/10.7554/elife.00243

7/31/2019 New twists in the unfolded protein response

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M`ll djklkbz | O`r xrj}x} jo xf` poeklh`h qtkx`jo t`}qko}

Mtk}} coh Tko/ Lje` 4134>39`1148=/ HKJ9 31/2008+`Lje`/1148= 8 ke 8

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http://dx.doi.org/10.7554/elife.00243http://dx.doi.org/10.7554/eLife.00048http://dx.doi.org/10.7554/eLife.00048http://dx.doi.org/10.7554/elife.00243