Selective inhibitor of IAP proteins

Selective inhibitor of IAP proteins

Apoptosis inhibitory proteins (IAPs) have often been considered inhibitors of cell death due to early reports describing their ability to bind directly and they inhibit caspases, the main factors that implement apoptosis. However, a greater understanding of the vital roles that PARs play as transduction intermediates in a diverse set of associated signaling cascades with functions ranging from the innate immune response to cell migration to the regulation of the cell cycle. In this review, we discuss the roles of IAPs in signaling, focusing primarily on cellular IAP proteins (c-IAPs).

The c-IAPs are important components in tumor necrosis factor receptor superfamily signaling cascades, including activation of the NF-jB family of transcription factors. As these receptors modulate cell proliferation and cell death, the involvement of c-IAPs in these pathways provides an additional means of controlling cell fate beyond simply inhibiting caspase activity. Furthermore, IAP-binding proteins, such as Smac and caspases, which have been described as having independent functions of cell death, can affect the activity of c-IAP in intracellular signaling. Collectively, the multifaceted functions and complex regulation of c-IAPs illustrate their importance as intracellular signaling intermediaries.

IAPs as regulators of cell signaling

As mentioned above, the functional scope of IAPs has expanded beyond caspase binding and cell death inhibition. IAPs have been implicated in various non-apoptotic signaling spectrums, ranging from the regulation of intracellular copper levels to control of cell cycle progression and cell migration. Furthermore, IAPs are important signal transduction factors in a variety of receptor-mediated pathways, many of which activate NF-jB.

As mentioned above, several members of the IAP family, including the c-IAP and XIAP, possess RING domains, which have been shown to be vital in many of the signaling cascades in which IAPs participate. On these signaling pathways, the IAPs, through their RING domains, function as E3 ubiquitin ligases, which are the final component in the enzymatic ubiquitination cascade. The consequences of labeling with two polyubiquitin chains, the chain linked to K63 and the chain linked to the K48 chain, have been well studied.

The chains are defined by the positions of the specific lysines within the ubiquitin-protein by which they are bound to its targets, and Paris has been shown to mediate ubiquitination of both K48 and K63. The K48  linked ubiquitin chain is generally considered a degradation signal that targets the labeled protein for Proteasome-mediated destruction. In contrast, K63 Polyubiquitination does not generally mediate proteasomal degradation but can act as a scaffold for the recruitment of additional factors to the signaling complex.

IAP and Smac mimetics

Receptor-mediated degradation of c-IAPs can be partially mimicked by a class of small molecule compounds based on the IAP-binding motif of Smac. These Smac (SM) mimetics, which are also known as IAP antagonists, bind to IAP and induce its degradation. Due to the connection between IAP and cell death, SM has been actively studied as potential therapeutic agents against cancer. While The ability of SMEs to release caspases from XIAP can contribute to the observed induction of cell death, this is now believed to represent only one aspect of his mechanism.

SMEs have been shown to target and degrade c-IAPs instead of XIAP, and although this does not exclude inhibition of XIAP, it suggests a more prominent role for c-IAPs in the regulation of SM-induced cell death. It is currently thought that SM-induced cell death is dependent on TNF.

More specifically, after SM treatment, c-IAPs are degraded and TNF is produced autocrine or in a paracrine manner, activating TNF-R1. However, in the absence of c-IAP1 / 2, ubiquitin scaffolds that help to form the receptor signaling complex cannot be correctly formed, resulting in RIP1 association with TRADD, FADD, and caspase-8 to form a signaling complex that induces cell death, resulting in caspase activation and cell death.

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