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1.
Figure 4

Figure 4. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Crosstalk between phosphorylation and ubiquitination promotes the degradation of Bim following brief preconditioning ischemia. Following ischemia, activation of p42/p44 MAPK promotes Bim phosphorylation. Phosphorylated Bim is ubiquitinated by its E3-ligase and degraded by the proteasome. The loss of Bim results in protection against further ischemia. What is unclear, is which E3-ligase mediates Bim ubiquitination following preconditioning ischemia.

Robert Meller. Neuroscientist. ;15(3):243-260.
2.
Figure 3

Figure 3. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Examples of ubiquitin chain remodeling. A20 mediates de-ubiquitination of Lys63 poly-ubiquitinated RIP-1. A20 can also catalyze the Lys48 poly-ubiquitination of RIP-1. At the proteasome the actions of de-ubiquitinating enzymes and E3-ligases can prevent a substrate from proteasome degradation, or extend the poly-ubiquitin chain and therefore enhance degradation.

Robert Meller. Neuroscientist. ;15(3):243-260.
3.
Figure 6

Figure 6. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Overview of preconditioning ischemia mediated morphological re-organization in dendrite and alterations in NMDA receptor mediated signaling. Following preconditioning ischemia, protein degradation and actin re-organization result in uncoupling of the NMDA receptor complexes from the actin cytoskeleton. The morphological and cytoskeleton changes results in an uncoupling of the toxic NMDA receptor mediated signaling but not physiological NMDA receptor function. As a result NMDA mediated excitotoxicity is reduced following preconditioning ischemia. This result may help identify how to switch off harmful NMDA receptor mediated signaling.

Robert Meller. Neuroscientist. ;15(3):243-260.
4.
Figure 5

Figure 5. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Overview of potential role of ubiquitin proteasome system in mediating the cellular response to ischemia. Brief ischemia can result in the rapid degradation of proteins by the proteasome and tolerance to ischemia. In contrast following harmful ischemia the accumulation of ubiquitinated proteins may contribute to cell stress. Harmful ischemia reduces proteasome function. The ubiquitinated proteins form aggregates which are subject to autophagic processing. Whether autophagy is a protective response or promotes further cell stress following ischemia is unclear.

Robert Meller. Neuroscientist. ;15(3):243-260.
5.
Figure 2

Figure 2. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Potential models of poly-ubiquitination. Sequential addition of ubiquitin refers to the process of ubiquitin transferring from the E1, to the E2 and then E3 ligase onto the substrate, this process would then be repeated for each additional ubiquitin added to the chain. However this model fails to describe how the E3-ligase which interacts with the substrate protein can physically reach the end of the ubiquitin chain. Some protein ubiquitination is mediated by multiple E3-ligases acting with the E3-ligase. The first E2-ligase mediates mono-ubiquitination, and the second E2-ligase promotes poly-ubiquitination. Some E2-ligases can assist in the transfer of pre-synthesized poly-ubiquitin onto the substrate. Finally, some proteins have E4 ligase activity. When added to the reaction, E4 ligases promote poly-ubiquitin chain extension.

Robert Meller. Neuroscientist. ;15(3):243-260.
6.
Figure 7

Figure 7. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Potential therapeutic sites of intervention based on ubiquitin proteasome mediated protection. Initial therapeutic strategies may target proteins whose rapid degradation is identified as being neuroprotective in rapid ischemic tolerance models. Delayed cell death has also been attributed to neuro-inflammation processes following ischemia. Proteasome inhibitors have shown to provide delayed therapeutic effects in reducing infarction and behavioral deficits by reducing neuro-inflammation. A combined therapeutic strategy targeting multiple processes which contribute to cell death following ischemia may effectively reduce brain injury following stroke. Time course figure adapted from (Dirnagl and others, 1999).

Robert Meller. Neuroscientist. ;15(3):243-260.
7.
Figure 1

Figure 1. From: The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance.

Structure of ubiquitin. Upper) Ubiquitin is synthesized as a precursor protein, whose c terminus is cleaved by a de-ubiquitinating enzyme to reveal a C-terminus glycine residue. Seven lysine residues are present in the primary amino acid structure of ubiquitin, which allows multiple potential poly ubiquitin chain linkages. Lower) Ubiquitin is added to a substrate protein by the sequential action of an E1-ligase, E2-ligase and an E3- ligase. The different poly-ubiquitin chains have different topologies, which are associated with their function. Ubiquitin chains with a Lys 48 linkage usually result in proteasomal degradation of the protein. Lys 63 linked chains can target proteins to the proteasome, lysosome or play a role in protein-protein interactions.

Robert Meller. Neuroscientist. ;15(3):243-260.

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