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Autophagy and p/SQSTM

Autophagy and p/SQSTM

Auutophagy to main page content HOME Probiotics and Eye Health SUBMIT SUBSCRIBE Ajtophagy AUTHOR INFO Autophagy and p/SQSTM CONTACT HELP Search for Keyword: GO. There Autohagy no association Autophagy and p/SQSTM age medianl/SQSTM category or stage Table 1. This is the first study demonstrating that p62 plays a role in host innate immune recognition of intracellular bacteria. A number of studies have shown a beneficial lifespan response to p62 overexpression, albeit with context-specific caveats. In S—GFP-p62 cells, immunostaining with an anti-CD63 antibody revealed colocalization with a fraction of the smaller GFP-p62 structures Fig. Autophagy and p/SQSTM



Autophagy and p/SQSTM -

LC3 puncta may mean activated autophagy, but also impaired autophagy due to a late stage block. Second, all autophagy markers may be associated with non-autophagic structures. This is in line with Inoue et al.

Similar correlations of high cytoplasmic p62 expression and adverse clinical features were also found in other cancer types, such as breast cancer [ 27 , 28 ], prostate cancer [ 29 ] and oral SqCC [ 25 ]. It is important to note, that this cytoplasmic and nuclear expression of p62 may not necessarily be linked to autophagy.

One alternative candidate effector may be the NRF2-KEAP1-pathway. Several groups could show that high levels of p62 lead to Nrf2 stabilization and subsequent transcription of genes with an antioxidant function [ 30 ]. Importantly, persistent activation of Nrf2 via p62 stabilization contributes to tumor progression [ 31 ].

However, in the study by Inoue et al. accumulation of p62 did not necessarily result in the stabilization of NRF2 [ 19 ]. Because increased p62 was shown to lead to NFκB-activation [ 32 , 33 ], another explanation for worse outcome may be the potentiation of NFκB-dependent transcription via p62 [ 19 ].

Whereas the cytoplasmic function of p62 is well studied its nuclear function remains less clear. It has been shown that p62 is a protein able to rapidly shuttle between nucleus and cytoplasm, although its preferential localization under homeostatic conditions is cytoplasmic.

In the nucleus p62 strongly co-localizes with PML-bodies and is probably involved in delivering ubiquitinated proteins for degradation [ 34 ].

Furthermore, p62 is involved in recruiting ALFY, a crucial factor for autophagic degradation of protein aggregates, from the nucleus to the cytoplasm [ 35 ]. It might well be that p62 is involved in recruiting other proteins to the cytoplasm as well. It remains to be investigated whether accumulation of p62 in the nucleus is cancer cell-specific, and if so, what functional consequences it may have.

Mislocalization of proteins in cancer cells is seen quite often. The best known is probably the predominant nuclear localization of NFκB in many cancer types [ 36 ]. In summary, this is the largest study to date reporting the expression of autophagy related markers LC3 and p62 in a well-defined, early-stage NSCLC cohort of cases.

We report the correlation of dot-like immunohistochemical staining for LC3 with LC3-II protein expression assessed by immunoblot analysis of the same FFPE archival cases, corroborating the feasibility to assess autophagy structures using immunohistochemistry. We observed a trend for better outcome in tumors with high dot-like staining of LC3 and p62, being surrogates for autophagic vacuoles and thus the process of autophagy, although low numbers of this subgroup might have precluded statistical significance.

Our results warrant further investigations concerning the link between expression data and functional autophagy states and a possible non-autophagy related role of p62 in NSCLC. The retrospective study included patients with primary resected node-negative early-stage NSCLC UICC 7 th edition stage IA-IIB [ 37 ], treated with curative surgery and diagnosed at the Institute of Pathology, University of Bern, Switzerland and the Institute of Pathology, University Hospital Basel, Switzerland between January and August The detailed staging work-up for this cohort of patients has already been reported [ 38 ].

After exclusion of cases with lymph node metastases, neoadjuvant treatment, rare tumor types other than AC, SqCC and LCC, and insufficient tumor tissue for further analysis, patients were finally included.

This retrospective study was approved by the local ethics committee. Median age of the patient cohort was 67 years range; years. The detailed distribution of clinic-pathologic characteristics can be seen in Tables 1 and 2.

A tissue microarray TMA was constructed as reported elsewhere [ 38 ]. In short, formalin fixed paraffin embedded FFPE tissue blocks were retrieved from the archives of the Institutes of Pathology. One punch diameter 0.

To assess for staining heterogeneity, 38 patients with positive and negative LC3 staining patterns were selected from the Bern sub-cohort. A TMA was constructed as reported elsewhere [ 39 ], using 8 cores diameter 0.

Additional punches 4 x 1 mm per tumor were taken for protein extraction. Immunohistochemical staining was performed using the automated system BOND RX Leica Biosystems, Newcastle, UK. TMA sections were cut at 4 μm, deparaffinized and rehydrated in dewax solution Leica Biosystems.

Endogenous peroxidase activity was blocked with H 2 O 2 solution for 4 minutes. All samples were incubated with the following primary antibodies for 30 minutes at room temperature RT , as described before [ 24 ]: LC3B from Cell Signaling Technology MA, USA, , clone D11, dilution , LC3 from Novus Biologicals Cambridge, UK, NB, dilution using Tris buffer pH 9 at 95°C for 30 minutes for antigen retrieval, p62 from MBL IL, USA, PM, dilution using Citrate buffer pH 6.

Read out of stainings was performed by AMS and SB as established before [ 24 ], and discrepancies were discussed on a multi-header microscope to gain a final consensus. Stone like structures SLS [ 20 ] were recorded separately.

Cytoplasmic p62 staining was scored as: 0 - no or very faint staining, 1 - weak staining, 2 - moderate to strong staining. Nuclear p62 staining was recorded as present or absent.

Images were acquired using a Zeiss Axioplan 2 microscope objective magnification 40 x and x and Axiovision software. The samples were deparaffinized and rehydrated using Xylene followed by descending alcohol series.

Samples were centrifuged and supernatant transferred to a new tube. Protein concentration was determined using the Bradford protein assay BioRad, Cressier, Switzerland. Total protein was visualized as loading control.

Membranes were incubated with primary antibodies over night at 4°C with shaking. Prior to visualization, membranes were incubated with Clarity Western ECL Substrate BioRad for 5 minutes at RT with shaking.

Descriptive and comparative statistical analyses were performed using the SPSS 23 software SPSS Inc, Chicago, IL, USA. Survival analysis was performed using log rank test and Cox regression analysis. The significance level was set at 0. The authors gratefully acknowledge the Translational Research Unit of the Institute of Pathology, University of Bern, for excellent technical support.

The work was supported by grants from Bernische Krebsliga to SB , Swiss Cancer League to RL, KLS and Stiftung für Klinisch-Experimentelle Tumorforschung Bern to MPT. Travis WD, Brambilla E, Burke AP, Marx A and Nicholson AG.

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Terje Johansen Terje Johansen. Correspondence: Terje Johansen terje. johansen uit. Author and article information. Publisher: Portland Press Ltd. Received: August 31 Revision Received: October 19 Accepted: October 19 Online ISSN: Published by Portland Press Limited on behalf of the Biochemical Society.

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Efficient Autpphagy is crucial for somatic maintenance, and its decline during l/SQSTM leads to p/SQQSTM dysfunction and disease. Selective autophagy is a Autophgay of autophagy mediated by Autophavy that An specific cargoes Efficient fat burning workouts Autophagy and p/SQSTM and is an essential Autophaty to maintain proteostasis. p62 Muscle preservation techniques best known PSQSTM its role in clearing protein aggregates via aggrephagy, but it has recently emerged as a receptor for other forms of selective autophagy such as mitophagy and lipophagy. Notably, p62 has context-dependent impacts on organismal aging and turnover of p62 usually reflects active proteostasis. In this review, we highlight recent advances in understanding the role of p62 in coordinating the ubiquitin-proteasome system and autophagy. We also discuss positive and negative effects of p62 on proteostatic status and their implications on aging and neurodegeneration. Finally, we relate the link between defective p62 and diseases of aging and examine the utility of targeting this multifaceted protein to achieve proteostatic benefits. Abbreviations Autophagy and p/SQSTM in this paper: ;/SQSTM, early endosome antigen 1; LC3, Autophagy and p/SQSTM Natural hair growth 3; PB1, Counteract fatigue naturally and Bem1p; siRNA, small Autophsgy RNA; Autophagy and p/SQSTM ubiquitin associated. J Cell Biol 21 November znd 4 Autophagy and p/SQSTM — Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. 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 coimmunoprecipitated 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.

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