Abstract
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.
Highlights
SQSTM1, the gene coding for the p62 protein, spans about 16 kb and is located on chromosome 5 [1,2]
The p62 protein is a beautiful paradigm for complexity in molecular biology
P62 interacts with several proteins regulating key pathways required for the maintenance of homeostasis of cells and tissues, as well as for inflammation and common diseases including cancer (Figure 4)
Summary
SQSTM1 (sequestosome 1), the gene coding for the p62 protein, spans about 16 kb and is located on chromosome 5 [1,2]. It is widely expressed and contains eight exons with a short 50 UTR (untranslated region) and an unusually long 30 UTR [3,4] (Figure 1). The expression of SQSTM1 is stress-associated and induced by the transcription factors Nrf, NF-κB, and MiT/TFE [8,9,10] Apart from their roles in melanocytes, members of the MiT/TFE (microphthalmia/transcription factor E) family of helix-loop-helix transcription factors are activated by different types of internal and external stresses and in cancer [11]
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