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Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug-induced toxicity in vitro.

Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug-induced toxicity in vitro.
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Alegre F, Moragrega ÁB, Polo M, Marti-Rodrigo A, Esplugues JV, Blas-Garcia A, Apostolova N,


Alegre F, Moragrega ÁB, Polo M, Marti-Rodrigo A, Esplugues JV, Blas-Garcia A, Apostolova N, (click to view)

Alegre F, Moragrega ÁB, Polo M, Marti-Rodrigo A, Esplugues JV, Blas-Garcia A, Apostolova N,

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British journal of pharmacology 2017 11 17() doi 10.1111/bph.14093

Abstract
BACKGROUND AND PURPOSE
SQSTM1/p62 is a multifunctional, stress-induced, scaffold protein involved in multiple cellular processes including autophagic clearance, regulation of inflammatory responses and redox homeostasis. Alterations in its function have been associated with a long list of human pathologies such as neurodegenerative, metabolic and bone diseases (down-regulation), and cancerogenesis (up-regulation). However, its role in the off-target effects of clinically used drugs is still not understood.

EXPERIMENTAL APPROACH
We have previously described the complex action that clinically relevant plasma concentrations of the antiretroviral drug Efavirenz (EFV) exert by on cultured human hepatic cells, which is manifested in mitochondrial dysfunction and ER stress/UPR, and paralleled by enhanced autophagy with functional autophagic flux at moderate EFV concentrations.

KEY RESULTS
p62 protein content is increased, an effect not observed in cells lacking functional mitochondria (rho(0) cells). p62 upregulation occurs due to enhanced SQSTM1 expression mediated through the transcription factor CHOP/DDIT3, while other well-known regulators (NF-kB and Nrf2) are not involved. We also explore the specificity of the effect of EFV on p62 by comparing it with those exerted by sublethal concentrations of other pharmacological stressors, chosen due to the similarities of their responses to those exerted by EFV. Our data suggest that p62 exerts a specific, autophagy-independent role and protects against EFV-induced mitochondrial ROS generation and NLRP3 inflammasome activation.

CONCLUSION AND IMPLICATIONS
These findings not only add to the existing knowledge of p62 as a multifunctional protein, but also harbor potential clinical implications as they may help to understand the off-target effects of pharmacological agents.

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