| dc.description.abstract |
<p>Cells thrive on sustaining order and balance to maintain proper homeostatic functions.
However, the primary machinery involved in protein quality control including chaperones,
ubiquitin proteasome system, and autophagy all decline in function and expression
with age. Failures in protein quality control lead to enhanced protein misfolding
and aggregation. Efficient elimination of misfolded proteins by the proteasome system
is critical for cellular proteostasis. However, inadequate proteasome capacity can
lead to aberrant aggregation of misfolded proteins and inclusion body formation, which
is a hallmark of numerous neurodegenerative diseases. Due to the post-mitotic nature
of neurons, they are more susceptible to the collapse in proteostasis correlated with
age. </p><p> </p><p>Here, we propose a cell based model of aggresome clearance using
a reversible proteasome inhibitor, MG132, to identify the precise molecular machinery
involved in proper processing of inclusions. It is known that once misfolded proteins
are aggregated, the proteasome system can no longer degrade them. Furthermore, the
continuous accumulation of aggregates often leads to aggresome formation, which results
in amalgamated inclusion bodies that are simply too large for autophagosomes to engulf
and degrade. Although, studies have shown that aggresomes can eventually be cleared
by autophagy, the molecular mechanisms underlying this process remain unclear. </p><p>Our
research reveals that regardless of impaired proteolysis, proteasomes can still stimulate
autophagy-dependent aggresome clearance by producing unanchored lysine (K)63-linked
ubiquitin chains via the deubiquitinating enzyme Poh1. Unanchored ubiquitin chains
activate ubiquitin-binding histone deacetylase 6, which mediates actin-dependent disassembly
of aggresomes. This crucial de-aggregation of aggresomes allows autophagosomes to
efficiently engulf and eliminate the protein aggregates. Interestingly, the canonical
function of Poh1 involves the cleavage of ubiquitin chains en bloc from proteasomal
substrates prior to their degradation by the 20S core, which requires intact 26S proteasomes.
In contrast, here we present evidence that during aggresome clearance, 20S proteasomes
dissociate from protein aggregates, while Poh1 and selective subunits of 19S proteasomes
are retained as an efficient K63 deubiquitinating enzyme complex. The dissociation
of 20S proteasome components requires the molecular chaperone Hsp90. Hsp90 inhibition
suppresses 26S proteasome remodeling, unanchored ubiquitin chain production, and aggresome
clearance. Ultimately, we hope to apply these molecular markers of inclusion body
processing to identify the underlying lesion in aggregate prone neurodegenerative
disease.</p>
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