bims-auttor 2019-08-11 papers

Issue of 2019–08–11
three papers selected by
Viktor Korolchuk, Newcastle University

FEBS J. 2019 Aug 06.

The endoplasmic reticulum (ER) is a large and dynamic cellular organelle. ER morphology consists of sheets, tubules, matrixes and contact sites shared with other membranous organelles. The capacity of the ER to fulfil its numerous biological functions depends on its continuous remodeling and the quality control of its proteome. Selective turnover of the ER by autophagy, termed ER-phagy, plays an important role in maintaining ER homeostasis. ER network integrity and turnover rely on specific ER-phagy receptors, which influence and co-ordinate alterations in ER morphology and the degradation of ER contents and membranes via the lysosome, by interacting with the LC3/GABARAP family. In this commentary, we discuss general principles and identify the major players in this recently characterized form of selective autophagy, while simultaneously highlighting open questions in the field. This article is protected by copyright. All rights reserved.

Keywords: ER-phagy; autophagy; endoplasmic reticulum; lysosome

DOI: https://doi.org/10.1111/febs.15031

Nat Commun. 2019 Aug 09. 10(1): 3623

MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat.

Ida Annunziata, Diantha van de Vlekkert, Elmar Wolf, David Finkelstein, Geoffrey Neale, Eda Machado, Rosario Mosca, Yvan Campos, Heather Tillman, Martine F Roussel, Jason Andrew Weesner, Leigh Ellen Fremuth, Xiaohui Qiu, Min-Joon Han, Gerard C Grosveld, Alessandra d'Azzo.

Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.

DOI: https://doi.org/10.1038/s41467-019-11568-0

Cancer Res. 2019 Aug 08. pii: canres.0708.2019. [Epub ahead of print]

CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival.

Laia Martínez-Carreres, Julien Puyal, Lucia C Leal-Esteban, Meritxell Orpinell, Judit Castillo-Armengol, Albert Giralt, Oleksandr Dergai, Catherine Moret, Valentin Barquissau, Anita Nasrallah, Angélique Pabois, Lianjun Zhang, Pedro Romero, Isabel Cristina Lopez-Mejia, Lluis Fajas.

Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor FLCN, regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacological inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation), and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncover a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-0708