Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

THE ENDOPLASMIC RETICULUM
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How do misfolded proteins in the ER signal to the nucleus? There are three parallel
pathways that execute the unfolded protein response (Figure 12–51A). The
first pathway, which was initially discovered in yeast cells, is particularly remarkable.
Misfolded proteins in the ER activate a transmembrane protein kinase in the
ER, called IRE1, which causes the kinase to oligomerize and phosphorylate itself.
(Some cell-surface receptor kinases in the plasma membrane are activated in a
(A)
ER LUMEN
CYTOSOL
ribonuclease
domain
three sensors for misfolded proteins
IRE1 PERK ER membrane ATF6
P P P P
kinase domain
PHOSPHORYLATION INACTIVATES
TRANSLATION INITIATION FACTOR
Figure 12–51 The unfolded protein
response. (A) By three parallel intracellular
signaling pathways, the accumulation of
misfolded proteins in the ER lumen signals
to the nucleus to activate the transcription
of genes that encode proteins that help
the cell cope with misfolded proteins in
the ER. (B) Regulated RNA splicing is a
key regulatory switch in pathway 1 of the
unfolded protein response (Movie 12.6).
REDUCTION OF
PROTEINS
ENTERING THE ER
REGULATED mRNA
SPLICING INITIATES
TRANSLATION OF
SELECTIVE
TRANSLATION OF
REGULATED PROTEOLYSIS
IN GOLGI APPARATUS
RELEASES
TRANSCRIPTION
REGULATORY PROTEIN 1
TRANSCRIPTION
REGULATORY PROTEIN 2
TRANSCRIPTION
REGULATORY PROTEIN 3
ACTIVATION OF GENES TO INCREASE
PROTEIN-FOLDING CAPACITY OF ER
(B)
1 MISFOLDED PROTEINS IN ER SIGNAL
THE NEED FOR MORE ER CHAPERONES.
THEY BIND TO AND ACTIVATE A
TRANSMEMBRANE KINASE
2 ACTIVATED KINASE UNMASKS AN
ENDORIBONUCLEASE ACTIVITY
3 ENDORIBONUCLEASE CUTS SPECIFIC
RNA MOLECULES AT TWO POSITIONS,
REMOVING AN INTRON
4 TWO EXONS ARE LIGATED TO
FORM AN ACTIVE mRNA
5 mRNA IS TRANSLATED TO MAKE A
TRANSCRIPTION REGULATOR
6 TRANSCRIPTION REGULATOR ENTERS
NUCLEUS AND ACTIVATES GENES
ENCODING ER CHAPERONES
misfolded proteins
1
kinase
domain
transmembrane
protein kinase
(sensor)
pre-mRNA
P
2
transcription
regulator
P
3
4
mRNA
exon exon
6
ER chaperone
ribonuclease
domain
5
intron
misfolded protein
bound to chaperone
7
nuclear pore
ER LUMEN
CYTOSOL
7 CHAPERONES ARE MADE IN ER,
WHERE THEY HELP FOLD PROTEINS
chaperone
gene
NUCLEUS
chaperone mRNA