Multifunctional p62 Effects Underlie Diverse Metabolic Diseases

Long, Min; Li, Xing; Li, Li; Dodson, Matthew; Zhang, Donna D.; Wang, Cong-Yi

doi:10.1016/j.tem.2017.09.001

Cited by 43 publications

(30 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dysregulation of SQSTM1 is also involved in multiple metabolic diseases (Long et al, 2017). SQSTM1 controls adipogenesis and body weight through regulation of ERK1 signaling (Lee et al, 2010;Rodriguez et al, 2006) and modulation of leptin signaling (Harada et al, 2013), respectively.…”

Section: Metabolic Diseasesmentioning

confidence: 99%

p62/SQSTM1 – steering the cell through health and disease

Sánchez‐Martín

Komatsu

2018

Journal of Cell Science

227

179

View full text Add to dashboard Cite

SQSTM1 (also known as p62) is a multifunctional stress-inducible scaffold protein involved in diverse cellular processes. Its functions are tightly regulated through an extensive pattern of post-translational modifications, and include the isolation of cargos degraded by autophagy, induction of the antioxidant response by the Keap1-Nrf2 system, as well as the regulation of endosomal trafficking, apoptosis and inflammation. Accordingly, malfunction of SQSTM1 is associated with a wide range of diseases, including bone and muscle disorders, neurodegenerative and metabolic diseases, and multiple forms of cancer. In this Review, we summarize current knowledge regarding regulation, post-translational modifications and functions of SQSTM1, as well as how they are dysregulated in various pathogenic contexts.

show abstract

Section: Metabolic Diseasesmentioning

confidence: 99%

p62/SQSTM1 – steering the cell through health and disease

Sánchez‐Martín

Komatsu

2018

Journal of Cell Science

227

179

View full text Add to dashboard Cite

show abstract

“…Our data, in addition to other studies (Jin et al , ), indicate that p62 interacts with ubiquitinated caspase‐8 and facilitates its aggregation and full activation. Since both p62 and TP53INP2 are involved in differentiation (Linares et al , ; McManus & Roux, ; Li et al , ; Sugiyama et al , ), apoptosis (Jin et al , ; Moscat & Diaz‐Meco, ; Bhattacharya et al , ), nuclear hormone receptor signaling (Baumgartner et al , ; Duran et al , ), diabetes (Sala et al , ; Kruse et al , ; Long et al , ), and autophagy (Pankiv et al , ; Moscat & Diaz‐Meco, ; Nowak et al , ; Mauvezin et al , ; Sancho et al , ), further studies are needed to unravel how they interplay/overlap in these pathways. Along the same line, TRAF6 has been implicated in multiple signaling pathways, such as autophagy, development, and immunity (Linares et al , ; Walsh et al , ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of death receptor signaling by the autophagy protein TP 53 INP 2

et al. 2019

View full text Add to dashboard Cite

TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in deathreceptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor-induced apoptosis. TP53INP2 binds caspase-8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspase-8 by TRAF6. We have defined a TRAF6-interacting motif (TIM) and a ubiquitin-interacting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspase-8 to TRAF6 for further polyubiquitination of caspase-8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspase-8, and subsequently reduce levels of death receptor-induced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAIL-induced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspase-8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway.

show abstract

“…To add a further layer of complexity studies mainly focused on human in pancreatic ductal carcinoma suggest that both p62 overexpression in cancer cells and its down regulation in tumour microenvironment promote tumour . In contrast, elevated p62 levels in the stroma seem to induce tumour suppression by intertwined anti‐inflammatory/metabolic responses . Thus, homeostatic maintenance of p62 in both cancer and stroma seems to dictate the final outcome of the tumorigenic process .…”

Section: Discussionmentioning

confidence: 99%

p62/SQSTM1 expression in canine mammary tumours: Evolutionary notes

Mariotti

Magi

Gavazza

et al. 2019

Vet Comparative Oncology

View full text Add to dashboard Cite

Recent studies highlighted the role of autophagy as a cardinal regulatory system for homeostasis and cancer-related signalling pathways. In this context, the deregulated expression of p62 -Sequestosome1 (p62/SQSTM1)a protein acting both as an autophagy receptor and signalling hub, has been associated with tumour development and chronic inflammation. Multiple clinical studies test drugs targeting autophagy, and even more research is on the way to clinical trials. However, no comparative investigations have been carried out to identify adequate preclinical models to assess p62-based medicine. In veterinary oncology the role of p62 in cancerrelated pathways has been largely ignored. We compared p62 sequences in multiple organisms and found that canine p62 significantly diverges from the humans and from other animals sequences. Then, we chart by immunohistochemistry the expression levels of p62 in canine mammary tumours. A total of 66 tumours and 10 nonneoplastic mammary samples were examined. The expression of p62 was higher in normal tissue and adenomas than carcinomas, with lowest levels of p62 protein detected in high grade carcinomas. In all cases examined the tumour stroma appeared to be p62-negative. Taken together our results would suggest that in dogs the association between p62 expression and cancer cells overturns that reported in human breast carcinoma, where p62 accumulates in malignant cells as compared to normal epithelium. Thus, at least in canine mammary tumours, p62 should be not considered a tumour-rejection antigen for an anti-cancer immunotherapy. K E Y W O R D Sautophagy, dog, gene homology, immunohistochemistry, mammary tumours, p62/SQSTM1

show abstract

Multifunctional p62 Effects Underlie Diverse Metabolic Diseases

Cited by 43 publications

References 81 publications

p62/SQSTM1 – steering the cell through health and disease

p62/SQSTM1 – steering the cell through health and disease

Regulation of death receptor signaling by the autophagy protein TP 53 INP 2

p62/SQSTM1 expression in canine mammary tumours: Evolutionary notes

Contact Info

Product

Resources

About