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 43

UPR

Apoptosis

Chaperones

BAX

BCL-2

If ER stress is resolved within
time window, cell survives. If
not, cell dies.

min - hours

BCL-2

BAX
Triggers commitment to apoptosis
(fast ~ 5 min)

Fig. 3. Model for the decision-making process between cell survival and death by the UPR. ER stress sensors, such as
IRE1, ATF6, and PERK, activate chaperone expression (protective) and apoptotic signaling pathways simultaneously. Over
time, apoptotic UPR signaling tilts the balance of anti- and proapoptotic BCL-2 proteins toward an excess of proapoptotic
BCL-2 proteins, committing the cell to apoptosis. If in this time window activation of chaperone and ERAD systems by the
UPR has remedied the cause for ER stress, and as a consequence turned off the UPR, the cell survives. Apoptosis ensues
if the UPR cannot relieve ER stress in the time required to tilt the BCL-2 protein balance in favor of pro-apoptotic BCL-2
proteins.

which could be destroyed by introducing ER stress activation-
impaired mutations ( 8 ). These data suggest that Ire1p is activated
by directly interacting with unfolded proteins. However, this
peptide-binding pocket is oriented toward the ER membrane.
In mammalian IRE1a, this pocket is too narrow for peptide
binding and access to this pocket is blocked by an a-helix ( 9 ),
arguing against a direct role for this pocket in unfolded protein
binding.
Once activated, ATF6 translocates to the Golgi complex
where its cytosolic bZIP transcription factor domain is proteolyti-
cally released by sequential cleavage by site-specific proteases 1
and 2 (S1P and S2P) ( 10 ). The cytosolic domain of ATF6 includ-
ing its bZIP and transcriptional activation domains translocates to
the nucleus where it activates transcription of ER chaperone
genes, genes involved in ERAD, phospholipid biosynthetic genes,
and acute phase response genes. Other type 2 transmembrane
bZIP transcription factors that contribute to the ER stress
response are BBF2H7, CREB3, CREB4, CREB-H, and OASIS.
An ATF6·CREB-H heterodimer activates acute phase and inflam-
matory genes ( 11 ). PERK signals via phosphorylation of at least
two proteins, the translation initiation factor eIF2a ( 12, 13 ) and