Protein Misfolding and Cellular Stress: An Overview - Protein Misfolding and Cellular Stress in Disease and Aging - page 4

The working mechanism of cytUPR has been intensively
studied ( 8-10 ). At non-stressed cellular conditions, components
of the PQC system are constitutively expressed in amounts suffi-
cient to counteract sporadic misfolding and accumulation of
newly synthesized proteins including defective translation prod-
ucts (DRiPs) ( 11, 12 ), as well as accumulation of moderately
damaged and oxidatively modified proteins.
The master regulator of cytUPR is the heat-shock factor 1
(HSF1). In non-stressed situations, HSF1 is present in an inactive
monomeric form in complex with chaperones, such as hsp90,
hsp70, and hsp40 ( 10, 13 ). During stress, unfolded proteins are
present in the cell, and HSF1 is activated. The mechanism of acti-
vation is conceptionally simple, but in reality complicated.
Accumulated unfolded proteins, either variant proteins caused by
gene variations or oxidatively modified proteins, which are not
easily degraded, may lead to sequestration of chaperones, espe-
cially hsp70 and hsp40 as well as hsp90, which also are involved
in the degradation process ( 14 ). Initially, the unfolded proteins
thereby compete with HSF1 for binding of chaperones, thus
releasing HSF1. Released HSF1 undergoes a conformational
change, trimerisation, becomes phosphorylated, and translocates
to the nucleus, where it binds to heat-shock elements (HSE) of a
large number of genes, including those coding for chaperones
( 10 ). In this way, the amounts of chaperones capable of occupy-
ing HSF1 increase. The activation is alleviated at the same time as
the unfolded proteins, assisted by the chaperones, may be refolded
or presented for the degradation apparatus. In addition to the
induction of chaperones, the HSF1 orchestrated stress response
also includes the important cytosolic antioxidant system, heme
oxygenase (HO-1), which converts heme to biliverdin that is fur-
ther metabolized to the powerful antioxidant bilirubin ( 9 ). This
reflects that oxidative stress is generated in stressed cells and that
combating it is important for cell survival. Indeed, recent results
have added significant knowledge to the mechanisms that may
alleviate the consequences of oxidative stress ( 15 ). Westerheide
and coworkers showed that HSF1 binding to and release from
the hsp70 promoter is dependent on acetylation of HSF1, which
is regulated by the metabolically controlled activity of the deacety-
lase SIRT1. Activation of SIRT1 by a high NAD + /NADH ratio,
which is present in metabolically active and healthy cells, hold
HSF1 in the binding competent form, thereby enhancing the
stress response and cell survival. Thus, the interplay between
HSF1 and SIRT1 together with other SIRT1 regulated transcrip-
tion factors, such as FOXO3, p53, and NF-kB, are thus involved in
the stress response, including combating of oxidative stress. Indeed,
the involvement of these cellular mechanisms may be seen as a
reflection of the importance of oxidative stress, perhaps the most
important, patophysiological manifestation in many diseases ( 16 ).