Abstract
p62 is a versatile protein involved in the delicate balance between cell death and survival, which is fundamental for cell fate decision in the context of both cancer and neurodegenerative diseases. As an autophagy adaptor, p62 recognizes polyubiquitin chains and interacts with LC3, thereby targeting the selected cargo to the autophagosome with consequent autophagic degradation. Beside this function, p62 behaves as an interactive hub in multiple signalling including those mediated by Nrf2, NF-κB, caspase-8, and mTORC1. The protein is thus crucial for the control of oxidative stress, inflammation and cell survival, apoptosis, and metabolic reprogramming, respectively. As a multifunctional protein, p62 falls into the category of those factors that can exert opposite roles in the cells. Chronic p62 accumulation was found in many types of tumors as well as in stress granules present in different forms of neurodegenerative diseases. However, the protein seems to have a Janus behaviour since it may also serve protective functions against tumorigenesis or neurodegeneration. This review describes the diversified roles of p62 through its multiple domains and interactors and specifically focuses on its oncoJanus and neuroJanus roles.
Highlights
P62 is a multifunctional protein that was originally identified as a component of the sequestosome, a cytoplasmic structure which serves as a storage place for ubiquitinated proteins. [1]
A common denominator for such a wide range of issues is represented by the balance between cell death and survival, which involves strategic crosstalk between apoptosis and autophagy, metabolic programming, redox balancing, and fine regulation of functional networks determining cell fate. p62 seems to take part in all of these processes and its contribution to their regulation is commonly considered noteworthy, as revealed by a number of studies correlating the factor to both cancer development and neurodegeneration
This review aims to highlight the double face of p62, critically discussing the most recent findings in the literature and evidencing the interconnections between pathways involved in cancer development and in neurodegenerative diseases
Summary
P62 is a multifunctional protein that was originally identified as a component of the sequestosome, a cytoplasmic structure which serves as a storage place for ubiquitinated proteins. [1]. Studies on selective protein degradation reveal a crucial role of p62 in autophagic digestion of poly-ubiquitinated protein cargo [9]. During the early steps of autophagosome formation, a dimeric form of p62 is phosphorylated in Ser407 by Atg1/ULK1 kinase, one of the upstream ATG gene products that trigger the autophagic flux This phosphorylation destabilizes the p62 dimer and renders the protein prone to undergo subsequent phosphorylation by other kinases (casein kinase or TANK-binding kinase1) to increase the binding affinity of p62 for ubiquitin chains [10]. P62 takes part in selective autophagy, and interacts with many factors that play important roles in determining cell fate.
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