p62/SQSTM1 – steering the cell through health and disease

Sánchez‐Martín, Pablo; Komatsu, Masaaki

doi:10.1242/jcs.222836

Cited by 218 publications

(178 citation statements)

References 178 publications

(202 reference statements)

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“…If, however, the amount of LC3-II further accumulates in the presence of lysosomal protease inhibitors, this would indicate enhancement of autophagic flux 56 . On the other hand, the protein expression level of p62/SQSTM1, a polyubiquitin binding protein, serves as an autophagic receptor and is a good indicator of autophagic flux [57][58][59] . Also, p62 protein expression has been used as an autophagic marker with LC3-II 60 .…”

Section: Discussionmentioning

confidence: 99%

“…Also, p62 protein expression has been used as an autophagic marker with LC3-II 60 . Although the p62 level alone is not indicative of activation of autophagy, p62 is also a marker for the degradation phase of autophagosomes and has a lot of functions beyond autophagy 59 . In the current study, our findings showed that loss of AKAP1 increased LC3-II protein expression but decreased p62 protein expression in AKAP1 −/− retina.…”

Section: Discussionmentioning

confidence: 99%

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Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

et al. 2020

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Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases in CaN and total Drp1 levels, as well as a decrease in Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

et al. 2020

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“…Beside its role in autophagy, p62 is a scaffolding hub for the cellular signalling pathways involving NF-kB activation, nerve growth factor signalling, and caspase activation (Sanchez-Martin & Komatsu, 2018).…”

Section: Introductionmentioning

confidence: 99%

Trichoplein controls endothelial cell function by regulating autophagy

Martello

Lauriola

Mellis

et al. 2019

Preprint

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Autophagy is an essential cellular quality control process that emerged critical for vascular homeostasis. Here we describe, the role for Trichoplein (TCHP) protein in linking autophagy with endothelial cells (ECs) function. The depletion of TCHP in ECs impairs migration and sprouting. TCHP directly binds PCM1, to regulate degradation of GABARAP, thus leading to a defective autophagy. Mechanistically, TCHP is indispensable for autophagosome maturation and its depletion resulted in the accumulation of SQSTM1/p62 (p62) and unfolded protein aggregates in ECs. The latter process is coupled to TCHP-mediated NF-kB activation. Of note, low levels of TCHP and high p62 levels were detected in primary ECs from patients with coronary artery disease. In addition, Tchp knock-out mice showed accumulation of p62 in the heart and cardiac vessels and reduced cardiac vascularization. Here, we reveal an autophagy-mediated mechanism for TCHP down-regulation, which poses a plausible target for regulation of endothelial function.

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“…The best known cellular function of p62 is as a selective autophagy receptor (Pankiv et al, 2007;Deretic, 2012). Separate from its actions in autophagy, p62 also plays a key role in a number of cellular signaling pathways that can profoundly affect cellular survival and growth (Sanz et al, 2000;Jin et al, 2009;Jain et al, 2010;Komatsu et al, 2010;Duran et al, 2011;Linares et al, 2013;Paul et al, 2014;Moscat et al, 2016;Goodall et al, 2016;Sanchez-Martin and Komatsu, 2018). Numerous studies have reported p62 over-expression in tumors and have associated elevated p62 expression with poor prognosis (Duran et al, 2008;Inui et al, 2013;Adams et al, 2016;Saito et al, 2016;Umemura et al, 2016;Karras et al, 2019;Nguyen et al, 2019;Polonen et al, 2019).…”

Section: Trim-mediated Deselective Autophagymentioning

confidence: 99%

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members

2020

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Autophagy is a cellular degradative process that has multiple important actions in cancer. Autophagy modulation is under consideration as a promising new approach to cancer therapy. However, complete autophagy dysregulation is likely to have substantial undesirable side effects. Thus, more targeted approaches to autophagy modulation may prove clinically beneficial. One potential avenue to achieving this goal is to focus on the actions of tripartite motif-containing protein family members (TRIMs). TRIMs have key roles in an array of cellular processes, and their dysregulation has been extensively linked to cancer risk and prognosis. As detailed here, emerging data shows that TRIMs can play important yet context-dependent roles in controlling autophagy and in the selective targeting of autophagic substrates. This review covers how the autophagyrelated actions of TRIM proteins contribute to cancer and the possibility of targeting TRIMdirected autophagy in cancer therapy.

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p62/SQSTM1 – steering the cell through health and disease

Cited by 218 publications

References 178 publications

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Trichoplein controls endothelial cell function by regulating autophagy

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members

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