The Nrf2 (nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2) transcription factor is a key player in cytoprotection and activated in stress conditions caused by reactive oxygen species (ROS) or electrophiles. Inflammasomes represent central regulators of inflammation. Upon detection of various stress factors, assembly of the inflamasome protein complex results in activation and secretion of proinflammatory cytokines. In addition, inflammasome activation causes pyroptosis, a lytic form of cell death, which supports inflammation. There is growing evidence of a crosstalk between the Nrf2 and inflammasome pathways at different levels. For example, Nrf2 activating compounds inhibit inflammasomes and consequently inflammation. This review summarizes what is known about the complex and predominantly antagonistic relationship of both stress-activated pathways.
p62 is a highly conserved, multi-domain, and multi-functional adaptor protein critically involved in several important cellular processes. Via its pronounced domain architecture, p62 binds to numerous interaction partners, thereby influencing key pathways that regulate tissue homeostasis, inflammation, and several common diseases including cancer. Via binding of ubiquitin chains, p62 acts in an anti-inflammatory manner as an adaptor for the auto-, xeno-, and mitophagy-dependent degradation of proteins, pathogens, and mitochondria. Furthermore, p62 is a negative regulator of inflammasome complexes. The transcription factor Nrf2 regulates expression of a bundle of ROS detoxifying genes. p62 activates Nrf2 by interaction with and autophagosomal degradation of the Nrf2 inhibitor Keap1. Moreover, p62 activates mTOR, the central kinase of the mTORC1 sensor complex that controls cell proliferation and differentiation. Through different mechanisms, p62 acts as a positive regulator of the transcription factor NF-κB, a central player in inflammation and cancer development. Therefore, p62 represents not only a cargo receptor for autophagy, but also a central signaling hub, linking several important pro- and anti-inflammatory pathways. This review aims to summarize knowledge about the molecular mechanisms underlying the roles of p62 in health and disease. In particular, different types of tumors are characterized by deregulated levels of p62. The elucidation of how p62 contributes to inflammation and cancer progression at the molecular level might promote the development of novel therapeutic strategies.
Inflammasome activation induces caspase-1edependent secretion of the proinflammatory cytokine IL-1b. In addition, caspase-1 activates the protein GSDMD in immune cells, causing pyroptosis, a lytic type of cell death. In contrast, UVB irradiation of human primary keratinocytes induces NLRP1 inflammasome activation, cytokine secretion, and caspase-1edependent apoptosis, rather than pyroptosis. Here, we addressed the molecular mechanisms underlying the role of caspase-1 in UVB-induced cell death of human primary keratinocytes. We show that GSDMD is a poor substrate of caspase-1 in human primary keratinocytes and that its activation upon UVB irradiation supports secretion of IL-1b. We screened for novel substrates of caspase-1 by a mass spectrometryebased approach and identified the specific cleavage of the major vault protein (MVP) at D441 by caspase-1 and-9. MVP is the main component of vaults, highly conserved ribonucleoprotein particles, whose functions are poorly understood. Cleavage of MVP is a common event occurring in human primary keratinocytes and fibroblasts undergoing apoptosis induced by different stimuli. In contrast, MVP cleavage could not be detected in pyroptotic cells. Cleavage of MVP by caspase-1 and-9 inactivates this cytoprotective protein. These results demonstrate a proapoptotic activity of caspase-1 and a crosstalk with caspase-9 upon inactivation of the cytoprotective MVP in apoptotic epithelial cells.
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