Review
Multifunctional p62 Effects Underlie Diverse Metabolic Diseases

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Trends

p62, as a ubiquitin binding protein and selective autophagy substrate, is well established as a key regulator in cancer and neurodegenerative diseases, etc. Recent research on p62 has shown that it may also play an important role in metabolic diseases.

p62 possesses multiple domains that regulate a range of metabolic processes, including adipogenesis, inflammation, BAT thermogenesis, insulin signaling, oxidative stress and apoptosis, energy, and nutrient balance. p62 may exert these effects in an autophagy-independent or -dependent manner.

Altered expression of p62 in patients with metabolic dysfunctions was observed, and this change has been linked with lipid, glucose and bone metabolism changes in genetically modified animals.

p62 participates in the regulation of multiple metabolic diseases, including obesity, T2DM, NAFLD, metabolic bone diseases, gout, atherosclerosis, and thyroid diseases, through regulating its downstream metabolic pathways.

p62, a protein capable of binding both ubiquitin and autophagy substrates, is well established as a key regulator in cancer and neurodegenerative diseases. Recently, there has been accumulating evidence that p62 is also a pivotal regulator in metabolic diseases, such as obesity, T2DM, NAFLD, metabolic bone disease, gout and thyroid disease. This review summarizes the emerging role of p62 on these diseases by considering its functional domains, phenotypes in genetically modified animals, clinically observed alterations, and its effects on downstream metabolic signaling pathways. At the same time, we highlight the need to explore the roles played by p62 in the gastrointestinal environment and immune system, and the extent to which its elevated expression may confer protection against metabolic disorders.

Introduction

p62, a 62 kDa protein initially identified as a phosphotyrosine-independent ligand for the Src homology 2 (SH2) domain of lymphoid-specific Src family tyrosine kinase p56lck [1], is also called sequestosome-1 (SQSTM1), as it is commonly localized to ubiquitinated protein aggregates [2] and sequestered into cytoplasmic inclusion bodies [3]. As a crucial mediator of basal cellular functions, p62 is widely expressed across tissue types, including the nervous, immune, reproductive, and endocrine systems [1]. p62 has been found to be expressed in several subcellular compartments, including the nucleus, autophagosomes, and lysosomes [2]. Previous investigations have reported that p62 plays an important role in two distinct intracellular protein degradation pathways, autophagy and the ubiquitin-proteasome system (UPS), both of which are involved in mediating cell survival [4]. Because of its classic function of delivering autophagic cargo, p62 expression is generally considered to inversely correlate with autophagic degradation and serve as a measure of autophagy flux [5]. At the same time, p62 also undergoes proteasomal degradation through Cul-3-mediated ubiquitination in UPS [6]. Due to the crucial role played by p62 in these two degradation systems, studies have established its involvement in a variety of diseases including cancer [7], amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD) [8].

Recently, a series of studies has hinted that p62 also participates in metabolic processes such as adipogenesis [9], insulin signaling [10], inflammation [11], oxidative stress 12, 13, apoptosis [14], brown adipose tissue (BAT) thermogenesis [15], and osteoclastogenesis [16], possibly independently of its functions in autophagy and UPS. These p62-linked processes are implicated in the morbidity of many metabolic diseases, including mature-onset obesity [17], type 2 diabetes mellitus (T2DM) [18], non-alcoholic fatty liver disease (NAFLD) [19], metabolic bone disease 16, 20, atherosclerosis [21], gout [22], and thyroid disease [23]. As such, further investigation into the significance of the functions of p62 in metabolic diseases is urgently needed.

Section snippets

The Metabolism-Related Domains of p62 (Autophagy-Independent and -Dependent)

Functional p62 is composed of 440 amino acids comprising more than 10 domains and putative binding sites [24], many of which are involved in metabolic processes. Several of these domains directly regulate metabolic processes independently of autophagy as described in Figure 1. At the N-terminal of p62, the SH2 domain interacts with the YXXM motif of insulin receptor substrate-1 (IRS-1) upon insulin stimulation in a similar manner to the IRS-1-p85 subunit of phosphatidylinositol 3-kinase (PI3k)

p62 Regulates Adipogenesis and Leptin Resistance

Although the role of p62 in obesity seems to be primarily in adipose tissue and the CNS, the control of obesity involves more than one organ or tissue. Adipose tissues from obese patients with T2DM and mice fed a high fat diet (HFD) have lower p62 protein levels 46, 51 and higher lipogenesis-related ERK activity 52, 53. Moreover, p62-KO leads to enhanced ERK activity and adipocyte differentiation to drive adult-onset obesity [17], which is corroborated by ERK1-KO [9]. These data demonstrate the

Perspective Remarks

Our review summarizes studies regarding the metabolic processes in which p62 participates in, and reveals a significant role for p62 in relevant lipid, glucose, and bone metabolism, etc., which implies p62 might be a potential target in metabolic diseases. For example, p62 has been reported as a potential pharmacological target in NAFLD patients [59], and a DNA plasmid encoding p62 has been indicated to be a new safe therapeutic option for inflammation-related bone loss diseases [20]. A

Disclaimer Statement

The authors have nothing to disclose.

Does the intervention of p62 overexpression have effects on metabolic diseases?

Does p62 have functional importance in regulating the gastrointestinal tract, gut microbiota, immune system, and lipid hormones?

How does p62 in adipose tissue affect the liver and muscle, such as via adipokines and proinflammatory cytokines?

How does p62 in the CNS interact with various peripheral tissues to maintain the body’s energy balance? Is this process mediated by

Acknowledgments

Supported by the National Natural Science Foundation of China (No. 81500647, No. 81471039 and No. 81270893), the Natural Science Foundation Project of Chongqing (CSTC2014jcyjjq10006 and CSTC2016jcyjA0502), the National Key R&D Program of China (No. 2016YFC1101100 and No. 2017YFC1309600), and the 2015 Young Doctor Diabetic Research Fund of International Medical Communication.

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