Article

Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A et al.. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603-614

Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway.
The Journal of Cell Biology (Impact Factor: 9.83). 12/2005; 171(4):603-14. DOI: 10.1083/jcb.200507002
Source: PubMed

ABSTRACT

Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and co-immunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

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    • "Ubiquitination seems to be particularly important to label cargo for autophagy, and a number of autophagy receptors with an ubiquitin-binding domain (such as p62/SQSTM1, NBR1, NDP52 or optineurin) have been identified, adding a level of plasticity and precision to the autophagy machinery (Stolz et al., 2014). p62/SQSTM1 is of particular interest because it is not only an important adapter protein for ubiquitinated cargo (Wurzer et al., 2015), but also a substrate for autophagic degradation (Bjorkoy et al., 2005; Komatsu et al., 2007a). Cells deficient in autophagy therefore often accumulate protein aggregates that contain p62, making this a widely used assay to detect autophagy deficits (Klionsky et al., 2012). "
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    ABSTRACT: Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain mal- formations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neuro- metabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss ‘congenital dis- orders of autophagy’ as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of heredi- tary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy- related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.
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    • "As LC3 is also degraded by autophagy, the interpretation of the LC3 amount alone is ambiguous (Mizushima et al., 2010). We therefore further evaluated the expression of p62, which is fused with autophagosomes through binding to LC3 directly and is degraded regularly during autophagy (Bjorkoy et al., 2005). Consistent with increased autophagic flux after spinal root avulsion, autophagic p62 was degraded in a time-dependent manner (Fig. 1B). "
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    ABSTRACT: Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is implicated in various pathological states in the nervous system. High-mobility group box 1 (HMGB1) is an inflammatory mediator known to be released into the local microenvironment from damaged cells. However, whether autophagy is induced and exogenous HMGB1 is involved in the process of spinal roots avulsion remain unclear. Here, we investigated the induction effect of autophagy and the possible role of HMGB1 during spinal root avulsion. It was found that autophagy was activated in the anterior horn of the spinal cord as represented by the increased expression of the autophagic marker microtubule-associated protein light chain 3-II (LC3-II), degradation of sequestosome 1 (p62), and formation of autophagosomes, and that autophagy was inhibited after intraperitoneal injection of anti-HMGB1 neutralizing antibodies in the rat spinal root avulsion model. In addition, HMGB1 induced autophagy and activated mitogen activated protein kinases (MAPKs) in primary spinal neurons, including c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK), and p38MAPK. Inhibition of JNK or ERK activity significantly blocked the effect of HMGB1-induced autophagy in primary spinal neurons. Finally, HMGB1-induced autophagy increased cell viability in primary spinal neurons under oxygen-glucose deprivation conditions. The above results suggest that HMGB1 is a critical regulator of autophagy and HMGB1-induced autophagy plays an important role in protecting spinal neurons against injury, which may provide new insights into the pathophysiological process of spinal root avulsion.
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    • "ATG8/LC3-II appears to have a role in membrane closure and is involved in cargo selection by recruiting cargo adaptor proteins, for example p62 and Nbr1, via their ATG8 interacting motif (AIM) or LC3 interacting region (LIR), respectively (Abounit et al., 2012; Birgisdottir et al., 2013; Nakatogawa et al., 2007; Weidberg et al., 2011). The process of cargo selection for degradation is best understood for p62, which can bind ubiquitinated proteins and deliver them through binding to ATG8/LC3-II to the growing autophagosome (Bjorkoy et al., 2005; Abounit et al., 2012). Oligomerization enables p62 to deliver several ubiquitinated proteins to a single ATG8/LC3-II molecule (Abounit et al., 2012). "
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    ABSTRACT: Autophagy is an ancient cellular pathway that is conserved from yeast to man. It contributes to many physiological and pathological processes and plays a major role in the degradation of proteins and/or organelles in response to starvation and stress. In the autophagic process cytosolic material is captured into double membrane-bound vesicles, the autophagosomes. After fusion with lysosomes, the cargo is degraded in the generated autolysosomes and then recycled for further use.
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