Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

Introduction
The ATG12-ATG5 complex then associates with ATG16 and is thought to create
a scaffold for the formation of the isolation membrane (Xie and Klionsky, 2007).
As autophagy functions by engulfing a portion of the cytoplasm, it was generally
thought to be a non-selective degradation system. However, this view has recently
been challenged by a number of reports which describe the specific targeting of
certain substrates to the autophagosome.
Misfolded Protein Stress, Aggresomes and the
Connection between Autophagy and the UPS
The existence of misfolded proteins in cells is an inevitable consequence of par-
tial unfolding during thermal or oxidative stress and of alterations in primary
structure caused by mutation, translational misincorporation or premature ter-
mination. Due to the exposure of hydrophobic regions, misfolded proteins are
prone to aggregation, and – if not immediately cleared – ultimately accumulate
in insoluble cytoplasmatic or nuclear inclusions (Kopito, 2000). The accumulation
of protein aggregates has been tightly linked to neuronal degeneration or organ
failure in a number of diseases such as Alzheimer’s, Parkinson’s or Huntington’s
disease and alcohol or drug induced liver damage (Gregersen et al., 2006). Al-
though the exact reasons behind the cytotoxicity of protein aggregates remain
unknown, a number of likely mechanisms have been proposed: First of all, the
accumulation of aggregates refractory to unfolding could lead to impairment of
the ubiquitin-proteasome system simply by “clogging” the proteasome, as the
unfolding of its substrates is a prerequisite for their degradation (Bence et al.,
2001; Bennett et al., 2005). Alternatively, aggregates could lead to the disruption
of microtubule-dependent axonal transport (Gunawardena et al., 2003), or they
could directly interact with transcription factors or membrane receptors, which
might result in an aberrant activation of signal transduction pathways (Yan et al.,
2000).
In any case, whatever the reason for the cytotoxicity of misfolded proteins, cells
have evolved a number of ways to counter the formation of protein aggregates.
First in line are the molecular chaperones, which transiently associate with un-
folded or partially folded intermediates and shelter hydrophobic surfaces from
forming inappropriate intra- or intermolecular contacts. Chaperones are con-
stitutively active in the quality control of nascent polypepdides, but can also be
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