Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex. Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. In this review, the process of autophagy is summarized, and the role of autophagy is discussed in a process-based manner.

http://genesdev.cshlp.org/content/21/22/2861.full.pdf

Autophagy: process and function

http://basicmed.med.ncku.edu.tw/admin/up_img/970425-1.pdf

Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice

Autophagy Inhibition Compromises Degradation of Ubiquitin-Proteasome Pathway Substrates

The ubiquitin–proteasome system (UPS) and autophagy are two distinct and interacting proteolytic systems. They play critical roles in cell survival under normal conditions and during stress. An increasing body of evidence indicates that ubiquitinated cargoes are important markers of degradation. p62, a classical receptor of autophagy, is a multifunctional protein located throughout the cell and involved in many signal transduction pathways, including the Keap1–Nrf2 pathway. It is involved in the proteasomal degradation of ubiquitinated proteins. When the cellular p62 level is manipulated, the quantity and location pattern of ubiquitinated proteins change with a considerable impact on cell survival. Altered p62 levels can even lead to some diseases. The proteotoxic stress imposed by proteasome inhibition can activate autophagy through p62 phosphorylation. A deficiency in autophagy may compromise the ubiquitin–proteasome system, since overabundant p62 delays delivery of the proteasomal substrate to the proteasome despite proteasomal catalytic activity being unchanged. In addition, p62 and the proteasome can modulate the activity of HDAC6 deacetylase, thus influencing the autophagic degradation.

/pdf/p62-links-the-autophagy-pathway-and-the-ubiqutin-proteasome-50tidwxvm9.pdf

p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation.

Autophagy is responsible for nonspecific, bulk degradation of cytoplasmic components. Recent work has revealed also that there is specific, autophagic degradation of polyubiquitinated protein aggregates, whose buildup occurs during neurodegenerative disease. Here, we report that simple mono-ubiquitination of normally long-lived cytoplasmic substrates is sufficient to target these substrates for autophagic degradation in mammalian cells. That is, upon their ubiquitination, both small [i.e., red fluorescent protein (RFP)] and large (i.e., peroxisomes) substrates are efficiently targeted to autophagosomes and then degraded within lysosomes upon autophagosome-lysosome fusion. This targeting requires the ubiquitin-binding protein, p62, and is blocked by the Class III phosphatidylinositol 3-kinase (PI3K) inhibitor, 3-methyladenine (3-MA), or by depletion of the autophagy-related-12 (Atg12) protein homolog. Mammalian cells thus use a common pathway involving ubiquitin and p62 for targeting diverse types of substrates for autophagy.

/pdf/ubiquitin-signals-autophagic-degradation-of-cytosolic-4y5851p7l8.pdf

Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes

Aggregated misfolded proteins are hallmarks of most neurodegenerative diseases In a chronic disease state, including pathologic situations of oxidative stress, these proteins are sequestered into inclusions Accumulation of aggregated proteins can be prevented by chaperones, or by targeting their degradation to the UPS If the accumulation of these proteins exceeds their degradation, they may impair the function of the proteasome Alternatively, the function of the proteasome may be preserved by directing aggregated proteins to the autophagy-lysosome pathway for degradation Sequestosome 1/p62 has recently been shown to interact with polyubiquitinated proteins through its UBA domain and may direct proteins to either the UPS or autophagosome P62 is present in neuronal inclusions of individuals with Alzheimer's disease and other neurodegenerative diseases Herein, we review p62's role in signaling, aggregation, and inclusion formation, and specifically as a possible contributor to Alzheimer's disease The use of p62 as a potential target for the development of therapeutics and as a disease biomarker is also discussed

/pdf/signaling-polyubiquitination-trafficking-and-inclusions-27jevia0li.pdf

Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62's role in neurodegenerative disease.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/j.febslet.2005.08.010

Michael G. Paine

Papers

Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62's role in neurodegenerative disease.

Evidence for p62 aggregate formation: role in cell survival.