bims-nocaut 2022-10-23 papers

Issue of 2022‒10‒23
two papers selected by
Quentin Frenger
University of Strasbourg

EMBO Rep. 2022 Oct 17. e202153552

Parkin drives pS65-Ub turnover independently of canonical autophagy in Drosophila.

Joanne L Usher, Alvaro Sanchez-Martinez, Ana Terriente-Felix, Po-Lin Chen, Juliette J Lee, Chun-Hong Chen, Alexander J Whitworth.

Parkinson's disease-related proteins, PINK1 and Parkin, act in a common pathway to maintain mitochondrial quality control. While the PINK1-Parkin pathway can promote autophagic mitochondrial turnover (mitophagy) following mitochondrial toxification in cell culture, alternative quality control pathways are suggested. To analyse the mechanisms by which the PINK1-Parkin pathway operates in vivo, we developed methods to detect Ser65-phosphorylated ubiquitin (pS65-Ub) in Drosophila. Exposure to the oxidant paraquat led to robust, Pink1-dependent pS65-Ub production, while pS65-Ub accumulates in unstimulated parkin-null flies, consistent with blocked degradation. Additionally, we show that pS65-Ub specifically accumulates on disrupted mitochondria in vivo. Depletion of the core autophagy proteins Atg1, Atg5 and Atg8a did not cause pS65-Ub accumulation to the same extent as loss of parkin, and overexpression of parkin promoted turnover of both basal and paraquat-induced pS65-Ub in an Atg5-null background. Thus, we have established that pS65-Ub immunodetection can be used to analyse Pink1-Parkin function in vivo as an alternative to reporter constructs. Moreover, our findings suggest that the Pink1-Parkin pathway can promote mitochondrial turnover independently of canonical autophagy in vivo.

Keywords: in vivo ; Parkinson's disease; mitochondria; mitophagy; phospho-ubiquitin

DOI: https://doi.org/10.15252/embr.202153552

J Oncol. 2022 ;2022 9253938

Unveiling the Noncanonical Autophagy-Independent Role of ATG7 and ATG9B in Head and Neck Squamous Cell Carcinoma (HNSCC).

Yibo Guo, Yiting Sun, Mingtao Chen, Yisheng Feng, Xu Zhang, Tong Ji, Zheqi Liu, Yu Zhang.

The role of autophagy in cancer remains elusive, and nontargeted autophagy inhibitors have limited therapeutic effects in HNSCC. Here, we systematically analyzed the correlation of autophagy-related genes in HNSCC through TCGA and single-cell sequencing data (GSE103322). ATG9B and ATG7 were found to have noncanonical autophagy-independent functions in HNSCC. Specifically, ATG9B was a protective factor in HNSCC patients through downregulating cancer cell EMT, and ATG7 was correlated with the immunosuppressive environment in HNSCC. Mechanistically, single-cell analysis revealed that ATG9B increased the epithelial phenotype of cancer cells but did not influence EMT signaling pathways. ATG7 was strongly correlated with elevated immunosuppressive checkpoints like PD-1, PD-L1, and CTLA4 in HNSCC. Further single-cell analysis and multiple immunofluorescence colocalization analyses indicated that ATG7 contributed to the high expression of PD-L1 in myeloid cells but not cancer cells. Collectively, our results revealed noncanonical autophagy-independent functions of autophagy-related genes. These results increase understanding of the intricacies of autophagy and may contribute to precision treatment using autophagy-targeted therapies.

DOI: https://doi.org/10.1155/2022/9253938