Abstract
Autophagy prevents cellular damage by eliminating insoluble aggregates of mutant misfolded proteins, which accumulate under different pathological conditions. Downregulation of autophagy enhances the inflammatory response and thus represents a possible common pathogenic event underlying a number of autoinflammatory syndromes, such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The pathogenesis of other monogenic or complex disorders that display symptoms of excessive inflammation also involve the autophagy pathway. Studies have shown that TRAPS-associated TNFRSF1A mutations induce cytoplasmic retention of the TNFR1 receptor, defective TNF-induced apoptosis, and production of reactive oxygen species (ROS). Furthermore, autophagy impairment may account for the pathogenic effects of TNFRSF1A mutations, thus inducing inflammation in TRAPS. In this review, we summarize the molecular interactions and functional links between autophagy with regard to nuclear factor-kappa B activation, ROS production, and apoptosis. Furthermore, we propose a complex interplay of these pathways as a model to explain the relationship between mutant protein misfolding and inflammation in genetically determined and aggregation-prone diseases. Accordingly, autophagy function should be investigated in all diseases showing an inflammatory component, and for which the molecular pathogenesis is still unclear.
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Acknowledgments
We are grateful to Dr. Anna Capurro (Direzione Scientifica, Istituto Giannina Gaslini) as well as Edanz Editing for the English editing of the manuscript. Tiziana Bachetti is a recipient of a 12-month fellowship awarded by the Fondazione Umberto Veronesi. This work was also supported by the Italian Ministry of Health (“Cinque per mille” and Ricerca Corrente to Istituto Giannina Gaslini) and by the Italian Association for Cancer Research (AIRC grants MFAG-11501 and GI-13217 to TB and IC, respectively).
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Bachetti, T., Ceccherini, I. Tumor necrosis factor receptor-associated periodic syndrome as a model linking autophagy and inflammation in protein aggregation diseases. J Mol Med 92, 583–594 (2014). https://doi.org/10.1007/s00109-014-1150-5
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DOI: https://doi.org/10.1007/s00109-014-1150-5