Biomedical Engineering Reference
In-Depth Information
of the PQC systems is assistance during folding of nascent
proteins, a main function is, together with the proteases and
antioxidant systems, to be the first line of cellular protection
against misfolded and damaged proteins due to internal or exter-
nal stressors. In young and healthy cells, the function and possi-
ble induction of these systems are sufficient to maintain
homeostasis and restore it if disturbed. However, in cells carry-
ing genetic defects and in stressed and ageing cells these “damage
protection” systems may be overloaded, and damaged and
misfolded proteins may accumulate in various forms. The result
is loss as well as gain of protein function, which may disturb a
variety of cellular functions, including oxidative balances, energy
production, and mitochondrial integrity, which may activate a
second line of defense, i.e., the elimination of accumulated pro-
teins and dysfunctional organelles, eventually initiating the cell
death mechanisms.
2. Cytosolic
Protein Quality
Control, Unfolded
Protein Response,
and Misfolded
Protein Overload
Proteins with functions in the cytosol, nucleus, and peroxisomes
emerge from the ribosome and fold in a concerted action (
1
). In
order to shield the hydrophobic parts from interacting with other
components of the crowded cellular environment, the emerging
polypeptides interact with a variety of chaperones and assistant
factors, i.e., nascent-polypeptide-associated complex (NAC), pre-
foldin, Hsp40, and Hsp70 (
2
). A subset also binds to the chaper-
onin TCP-1 ring complex (TRiC) and is held in a folding-competent
state until released from the ribosome (
3
). The majority of small
cytosolic proteins complete their folding without further assis-
tance, whereas a fraction requires further assistance from the
chaperone Hsp90 and the chaperonin TRiC (
2
). If the native
structure is not easily achieved, the interaction with TRiC may be
prolonged, and the polypeptide, which may be arrested in an
intermediate conformation (
3
), is presented for the degradation
components of the cytosolic PQC system: the ubiquitin-proteasome
system (UPS), which functions as a safeguard for acquisition
of functional conformers of nascent proteins by eliminating
potentially toxic conformers (
4, 5
). This is only one of the
mechanisms exerted by the PQC system. Another is “damage
protection,” which was first described for the cytosol as the cyto-
solic heat-shock response (
6
). This is a dynamic and very complex
system, which could be coined the cytosolic unfolded protein
response (cytUPR) to indicate the functional similarity to the
endoplasmatic reticulum UPR (erUPR) and the mitochondria
UPR (mitUPR) (
7
).
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