p62/SQSTM1 at the interface of aging, autophagy, and disease

Abstract

Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

“…In addition, several studies have identified changes with age in signaling pathways (i.e. mTOR, SIRT, FOXO) that could contribute to reduced induction of autophagy and autophagosome formation (Bitto et al., 2014; Park et al., 2016; Perluigi, Di Domenico & Butterfield, 2015; Schiavi & Ventura, 2014). Future analysis will be required to explore the molecular requirements that determine the recruitment of motor proteins to AVs and LYS and the potential impact in this process of age‐associated changes in these signaling routes.…”

Role of autophagy in methylmercury-induced neurotoxicity in rat primary astrocytes

“…This may be due to MeHg-induced inhibition of p62 by lysosomal disruption (Daré et al, 2001; Tofighi et al 2011). p62 has multiple domains to regulate cellular events (Bitto et al, 2014; Wang et al 2014), and may trigger nuclear factor-κB (NF-κB) activity to promote cell survival responses (Chen et al 2014). Thus, the significance of enhanced p62 protein by MeHg needs further study.…”

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

“…As p62 appears to play an important role in maintaining mitochondrial quality control through mitophagy, it is possible that the loss of p62 in pancreatic β cells may cause mitochondrial dysfunction and thus result in impaired glucose tolerance [5]. Normal β-cell function and mass in β-cell-specific p62-deficient mice suggested redundant autophagy receptors; for instance, NBR1, which shares similar functional domains with p62, may have a compensatory role in mitophagy when p62 is deficient [26].…”

“…Therefore, elucidating the molecular mechanisms underlying pancreatic β-cell dysfunction is a key to understanding the pathology of diabetes [3,4]. Sequestosome 1 (SQSTM1, referred to hereafter as p62) is a multifunctional scaffold protein that can interact with several signaling pathways through its functional subdomains, including the Phox and Bem1 (PB1) domain, zinc-finger domain, TNF receptor-associated factor 6 (TRAF6)-binding domain, and Kelch-like ECHassociated protein 1 (Keap1) interacting region (KIR) [5][6][7]. p62/SQSTM1 can activate the antioxidant response by interacting with the Keap1-Nrf2 pathway [8][9][10].…”

“…p62 -/-mice have a reduced lifespan and show premature aging phenotypes with increased mitochondrial damage and dysfunction [21]. Given the importance of p62 in maintaining mitochondrial homeostasis through the autophagic degradation of damaged mitochondria, or so called mitophagy, it is possible that loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction and thereby reduces insulin release, resulting in impaired glucose tolerance [5]. On the other hand, a recent study reported that in contrast to what has been reported for ubiquitin-induced pexophagy and xenophagy, p62 appears to be dispensable for mitophagy [22].…”