![]() ![]() In contrast, certain components of the autophagy machinery can also promote inflammatory processes such as scaffolding the activation of RIPK1 and RIPK3 18. For instance, damaged mitochondria, the source of oxidative stress, are eliminated by autophagy 17. One reason for the overlap between autophagy and these or other cell stress pathways is that autophagy can serve as an effector to eliminate the danger. Furthermore, oxidative stress induces autophagy and promotes the expression of autophagy factors through activation of Nrf2-dependent transcription 16. TBK-1, a kinase required for activation of IRF-3 in response to viral infection, promotes autophagosome formation, maturation, and selective cargo recognition by the autophagy apparatus 12- 15. For example, activation of components of the NF-κB pathway can promote autophagy through several mechanisms 8- 11. There are numerous connections between the autophagy machinery and other cellular stress response pathways. Higher organisms have a substantially larger repertoire of autophagy factors 7, possibly owing to the expanded physiological roles of autophagy in multicellular organisms. ![]() Several dozen proteins have been identified to have roles in autophagy in yeast. Typically, autophagosomes fuse with lysosomes resulting in the degradation of vesicular contents 6. Macroautophagy (hereafter referred to as autophagy) is a mechanism of cellular waste management and quality control in which cytoplasmic contents are packaged in a double membranous vesicle termed an autophagosome 6. SynopsisĪctivation of the macroautophagy pathway frequently accompanies a wide variety of cellular hazards including nutrient limitation, proteotoxic stress, damage to endolysosomal membranes, and detection of pathogens or pathogen-associated molecular patterns (PAMPs) 1- 5. This ability of TAK1 to disable p62 as an autophagy receptor may allow certain autophagic substrates to accumulate when needed for cellular functions. Thus, TAK1 governs p62 action, switching it from an autophagy receptor to a signaling platform. On the other hand, p62 facilitates the assembly and activation of TAK1 complexes, suggesting a connection between p62's signaling functions and p62 body formation. TAK1 also relocalizes p62 into dynamic cytoplasmic bodies, a phenomenon that accompanies the stabilization of TAK1 complex components. TAK1 reduces p62 localization to autophagosomes, dampening the autophagic degradation of both p62 and p62-directed autophagy substrates. Here, we show that TAK1, a kinase involved in immune signaling, negatively regulates p62 action in autophagy. How these seemingly disparate functional roles of p62 are coordinated has not been resolved. The protein p62/Sequestosome 1 (p62) has been described as a selective autophagy receptor and independently as a platform for pro-inflammatory and other intracellular signaling. ‡ These authors contributed equally to this work.6 Present address: Biochemistry and Molecular Biology Graduate Program, University of Maine, Orono, ME, USA.5 Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.4 Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.3 UC Davis Genome Center, University of California Davis, Davis, CA, USA.2 Biomedical Sciences Graduate Program, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.1 Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. ![]()
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