Abstract
Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14’s UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome’s activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential.
Highlights
That Activate 26S Proteasomes and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA; Abstract: ubiquitination is widely assumed to be the only regulated step in the ubiquitin
During our efforts to understand how substrate de-ubiquitination on the proteasome may be linked to the ATP-dependent proteolytic steps, Andreas Peth found that the binding of a ubiquitin conjugate to the proteasomal deubiquitinating enzymes, Usp14/Ubp6 or
Because ZFAND5 interacts with both ubiquitin and proteasomes and accelerates the hydrolysis of ubiquitinated proteins, ZFAND5 may serve on the proteasome as an additional binding site for ubiquitinated substrates, or it may function in an analogous manner to a shuttling factor to deliver certain ubiquitin conjugates to the proteasome and activate its degradative capacity
Summary
Our lab has focused on furthering our understanding of the 26S proteasome, both because of its key role in intracellular proteolysis and because of its intriguing molecular mechanisms. Our findings that PKA and PKG, which regulate a large diversity of physiological processes, activate the proteasome and accelerate the degradation of many cell proteins within minutes represent new aspects of their function [16,17]. These findings have raised many fundamental questions and even opened up new opportunities for therapeutic interventions. Pharmacological treatments that raise cAMP or cGMP, enhancing the degradation of the misfolded, mutated proteins, represent very promising new approaches to combat proteotoxic diseases, as discussed below These findings have altered the way we should view the ubiquitin–proteasome system’s functioning in mammalian tissues. The physiological significance of such regulation and its potential medical applications are still largely unexplored
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