Consequences of Stress in the Secretary Pathway: The ER Stress Response and Its Role in the Metabolic Syndrome - Protein Misfolding and Cellular Stress in Disease and Aging - page 44

the bZIP transcription factor NRF2 ( 14, 15 ). Phosphorylation of
eIF2a attenuates general translation and serves to decrease the
influx of nascent, unfolded polypeptide chains into the ER.
Translational attenuation also clears short-lived proteins from
the cell, including D-type cyclins and the NF-kB inhibitory IkB
proteins. Loss of D-type cyclins causes cell cycle arrest in G 1 ( 16 ).
Depletion of IkB activates the transcription factor NF-kB ( 17 )
and subsequently innate immune response, inflammatory, and
antioxidant genes ( 18, 19 ). eIF2a phosphorylation promotes
translation of mRNAs containing several short upstream open
reading frames in their 5¢ untranslated region, for example, the
mRNA for the transcription factor ATF4 ( 20 ). ATF4, in concert
with NRF2, activates an antioxidant response, induces the
inhibitor of mRNA 5¢-cap-binding protein 4E-BP1 ( 21 ), and the
proapoptotic transcription factor CHOP ( 22 ). Induction of
4E-BP1 contributes to translational arrest. CHOP induction is
countered by induction of antioxidant response genes, such as
glutathione S -transferase and heme-oxygenase 1 ( 23 ), and stimu-
lation of translation of cIAP1/hIAP2 mRNA ( 24, 25 ), encoding
an inhibitor of apoptosis. Translational attenuation during ER
stress is transient. eIF2a phosphorylation is countered by induc-
tion of GADD34 , encoding a regulatory subunit of protein
phosphatase 1 (PP1) that directs PP1 toward phosphorylated
eIF2a ( 26 ). gadd34 − / − cells are protected from ER stress-induced
cell death, suggesting that early recovery from translational
arrest contributes to apoptotic cell death ( 27 ), possibly via
the activation of apoptotic signaling in response to elevated ER
stress.
IRE1a initiates non-spliceosomal splicing of the mRNA for
the bZIP transcription factor XBP-1 ( 28-31 ). XBP-1 contributes
to full induction of many chaperone and protein foldase genes
such as BiP , GRP94 , p58 IPK , ERdj4 , ERO1-L a, -b, and ERP72
( 32, 33 ). XBP-1 increases the activity of phosphocholine cytidyl-
transferase ( 34 ), the rate-limiting enzyme for phosphatidylcho-
line synthesis. An XBP-1·ATF6 heterodimer induces genes
involved in ERAD ( 35, 36 ). IRE1 also triggers inflammatory and
apoptotic signaling via activation of MAP kinase modules, leading
to the activation of the MAP kinases JNK and p38. Activation of
these MAP kinases by IRE1 requires its interaction with the
adaptor protein TRAF2 ( 37 ). TRAF2 is a member of the TRAF
protein family, which encompasses six different proteins in humans.
TRAF proteins contain a C -terminal TRAF domain which mediates
their interactions with transmembrane receptors. The N -terminal
coiled-coil portion of the TRAF domain is required for homo-
and heterotrimer formation. The N -terminal effector domains of
TRAF2, a RING domain which may possess ubiquitin ligase
activity, and five Zn 2+ -ingers are required for the activation of
JNK and NF-kB by TRAF2 ( 38 ). In the UPR, TRAF2 activates