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Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

1
Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago 7510157, Chile
2
Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5110566, Chile
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(14), 3379; https://doi.org/10.3390/ijms20143379
Received: 31 May 2019 / Revised: 26 June 2019 / Accepted: 1 July 2019 / Published: 10 July 2019
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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Abstract

Proteasome inhibitors have been actively tested as potential anticancer drugs and in the treatment of inflammatory and autoimmune diseases. Unfortunately, cells adapt to survive in the presence of proteasome inhibitors activating a variety of cell responses that explain why these therapies have not fulfilled their expected results. In addition, all proteasome inhibitors tested and approved by the FDA have caused a variety of side effects in humans. Here, we describe the different types of proteasome complexes found within cells and the variety of regulators proteins that can modulate their activities, including those that are upregulated in the context of inflammatory processes. We also summarize the adaptive cellular responses activated during proteasome inhibition with special emphasis on the activation of the Autophagic-Lysosomal Pathway (ALP), proteaphagy, p62/SQSTM1 enriched-inclusion bodies, and proteasome biogenesis dependent on Nrf1 and Nrf2 transcription factors. Moreover, we discuss the role of IRE1 and PERK sensors in ALP activation during ER stress and the involvement of two deubiquitinases, Rpn11 and USP14, in these processes. Finally, we discuss the aspects that should be currently considered in the development of novel strategies that use proteasome activity as a therapeutic target for the treatment of human diseases. View Full-Text
Keywords: proteasome; immunoproteasome; autophagy proteasome; immunoproteasome; autophagy
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Albornoz, N.; Bustamante, H.; Soza, A.; Burgos, P. Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond. Int. J. Mol. Sci. 2019, 20, 3379.

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