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.