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The left half of the figure represents the state of several proteins and mRNAs under normal conditions, the right half shows the activation of the UPR in
response to an overload of the ER with unfolded or malfolded proteins. Under normal conditions the three effector proteins of the UPR (PERK, IRE1 and
ATF6) are inactive. Under such conditions the expression of ATF4 and XBP1 are low due to the regulatory elements in their corresponding mRNAs.
Activation of the UPR leads to dimerization of PERK and IRE1, which leads to autophosphorylation and activation of the proteins. Active PERK
phosphorylates eIF2, leading to a reduced rate of general protein synthesis and to increased translation of the mRNA of transcription factor ATF4. The
endoribonuclease activity of IRE1 removes a small inhibitory RNA element from the mRNA of XBP1, leading to a splice variant of XBP1, which is also a
Source: Vanishing White Matter, The Online Metabolic and Molecular Bases of Inherited Disease
transcription factor. The chaperone BiP is released from growing polypeptide chains, which are entering the ER, and from target proteins such as ATF6.
Citation:
BeaudetofAL,
Vogelstein
B, Kinzler
KW, Antonarakis
Ballabio
Gibson
K, Mitchell
G. The Online
Metabolic
andportion
Molecular
The release from
BiP Valle
allowsD,transport
ATF6
to the Golgi
apparatus.
SubsequentSE,
cleavage
byA,
the
S1P and
S2P proteases
liberates
an effector
of
Bases
of
Inherited
Disease;
2014
Available
at:
http://mhmedical.com/
Accessed:
August
03,
2017
ATF6, allowing it to translocate to the nucleus. The transcription factors ATF6, ATF4 and XBP1 increase transcription of mRNAs coding for proteins that
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McGraw-Hill
Education.
All rights
reserved
are involved Copyright
in counteracting
toxic effects
of denatured
proteins
and in re-establishing normal physiological conditions in the ER or promote cell cycle
arrest and apoptosis.