bims-auttor 2019-06-09 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2019–06–09
nine papers selected by
Viktor Korolchuk, Newcastle University

mTOR Senses Intracellular pH through Lysosome Dispersion from RHEB.
Hyperosmotic stress induces unconventional autophagy independent of the Ulk1 complex.
The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells.
TP53INP2 mediates autophagic degradation of ubiquitinated proteins through its ubiquitin-interacting motif.
Non-histone human chromatin protein PC4 is critical for genomic integrity and negatively regulates autophagy.
Autophagy and mitophagy in cancer metabolic remodelling.
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes.
Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition.
Mitochondria as playmakers of apoptosis, autophagy and senescence.

Bioessays. 2019 Jun 03. e1800265

mTOR Senses Intracellular pH through Lysosome Dispersion from RHEB.

Zandra E Walton, Rebekah C Brooks, Chi V Dang.

  Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three-decade-old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now independently reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTOR-governed synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation.

Keywords:  Ras homolog enriched in brain (RHEB); acidity; cancer immunity; circadian clock; lysosome trafficking; mechanistic target of rapamycin (mTOR); pH

DOI:  https://doi.org/10.1002/bies.201800265
Mol Cell Biol. 2019 Jun 03. pii: MCB.00024-19. [Epub ahead of print]

Hyperosmotic stress induces unconventional autophagy independent of the Ulk1 complex.

Naoki Tamura, Shun Kageyama, Masaaki Komatsu, Satoshi Waguri.

Autophagy is considered an adoptive mechanism against hyperosmotic stress. Although the process has been reported to be triggered by the inhibition of mTORC1, the precise downstream mechanisms remain elusive. Here, we demonstrate that hyperosmotic stress-induced autophagy is different from conventional macroautophagy in mouse embryonic fibroblasts (MEFs) and human T24 cells. Our results indicated that cytoplasmic puncta for isolation membrane markers WIPI2 and Atg16L increased after hyperosmotic stress. They were found to partially colocalize with puncta for a selective autophagy substrate, SQSTM1/p62, and were shown to be diminished by inhibitors for phosphatidylinositol 3-kinase (PI3K), or by knockdown of hVps34, a component of PI3K. In addition, flux assays showed that SQSTM/p62 and NcoA4 were degraded by the lysosomal pathway. Surprisingly, Ulk1 that is essential for starvation-induced macroautophagy, remained inactivated under hyperosmotic stress, which was partially contributed by mTOR activity. Accordingly, the Ulk1 complex was not nucleated under hyperosmotic stress. Finally, autophagy proceeded even in MEFs deficient in FIP200 or Atg13, which are components of the Ulk1 complex. These data suggest that hyperosmotic stress-induced autophagy represents an unconventional type of autophagy that bypasses Ulk1 signaling.

DOI: https://doi.org/10.1128/MCB.00024-19
Cell Signal. 2019 May 31. pii: S0898-6568(19)30124-X. [Epub ahead of print]

The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells.

Mai Shi, Shuang Yang, Xinwang Zhu, Da Sun, Dan Sun, Xue Jiang, Congxiao Zhang, Lining Wang.

  Renal aging and associated functional decline are associated with an increase in cellular senescence. Previous studies show a direct correlation between advanced glycation end products (AGEs) accumulation and renal aging, chronic kidney disease (CKD) and other nephropathies, although the underlying molecular mechanisms remain largely unclear. We found elevated levels of the receptor of advanced glycation end product (RAGE) as well as STAT5 in aged human kidneys, as well as in human mesangial cells aged artificially through AGEs. Furthermore, genetic and pharmacological ablation of STAT5 significantly downregulated p16 levels and the percentage of β-Gal-positive senescent cells in mesangial cells and kidneys of SD rats, indicating that AGEs-induced senescence depends on STAT5 signaling. The aged kidney tissues (both in patients and SD rats) and mesangial cells show low levels of LC3 (both LC3-II and LC3-II/I), and cultured mesangial cells also show fewer autolysosomes, autophagosomes, and autophagic vacuoles, which can be partially restored upon STAT5 inhibition. This indicates that AGEs accumulation also obliterates the protective effects of autophagy against aging via the RAGE/STAT5 axis. Direct inhibition of autophagy via 3-methyladenine (3-MA) increases the phenotype of renal aging without activating RAGE, it is inhibition of autophagy caused by RAGE/STAT5 that leads to mesangial aging. In conclusion, we found AGEs induced inhibition of autophagy and cellular senescence in mesangial cells via the RAGE/STAT5 pathway. Moreover, we found that RAGE/STAT5 acts as a key link between autophagy and senescence in the process of mesangial aging in vivo and in vitro.

Keywords:  Aging; Autophagy; Kidney; Losartan; STAT5

DOI:  https://doi.org/10.1016/j.cellsig.2019.05.019
FEBS Lett. 2019 Jun 03.

TP53INP2 mediates autophagic degradation of ubiquitinated proteins through its ubiquitin-interacting motif.

Yinfeng Xu, Wei Wan.

  The tumor protein p53-inducible nuclear protein 2 (TP53INP2) has been reported to participate in autophagy by interacting with autophagosome-localized Atg8 family proteins, including LC3. Here, we uncover a novel function for TP53INP2 in the autophagic degradation of proteins. We identify the ubiquitin-interacting motif (UIM) of TP53INP2 that mediates its binding to ubiquitin and ubiquitinated proteins. TP53INP2 lacking the UIM is able to displace autopahgic adaptor p62 from LC3, which leads to accumulation of ubiquitinated proteins in cells. Furthermore, overexpression of TP53INP2 lacking the UIM sensitizes cells to chloroquine treatment. Our findings indicate that TP53INP2 may act as a novel autophagic adaptor through recruiting ubquitinated substrates to autophagosomes for degradation. This article is protected by copyright. All rights reserved.

Keywords:  LC3; TP53INP2; adaptor protein; autophagy

DOI:  https://doi.org/10.1002/1873-3468.13467
FEBS J. 2019 Jun 06.

Non-histone human chromatin protein PC4 is critical for genomic integrity and negatively regulates autophagy.

Sweta Sikder, Sujata Kumari, Pallabi Mustafi, Nisha Ramdas, Swatishree Padhi, Arka Saha, Utsa Bhaduri, Birendranath Banerjee, Ravi Manjithaya, Tapas K Kundu.

  Multifunctional human transcriptional positive co-activator 4 (PC4) is a bona fide non-histone component of the chromatin and plays a pivotal role in the process of chromatin compaction and functional genome organization. Knockdown of PC4 expression causes a drastic decompaction which leads to open conformation of the chromatin, and thereby altered nuclear architecture, defects in chromosome segregation and changed epigenetic landscape. Interestingly, these defects do not induce cellular death but result in enhanced cellular proliferation, possibly through enhanced autophagic activity. Moreover, PC4 depletion confers significant resistance to gamma irradiation. Exposure to gamma irradiation further induced autophagy in these cells. Inhibition of autophagy by small molecule inhibitors as well as by silencing of a critical autophagy gene drastically reduces the ability of PC4 knockdown cells to survive. On the contrary, complementation with wild type PC4 could reverse this phenomenon, confirming the process of autophagy as the key mechanism for radiation resistance in absence of PC4. These data connect the unexplored role of chromatin architecture in regulating autophagy during stress conditions such as radiation. This article is protected by copyright. All rights reserved.

Keywords:  AMPK pathway; Chromatin dynamics; Histone acetylation; autophagy inhibition; gamma radiation resistance

DOI:  https://doi.org/10.1111/febs.14952
Semin Cell Dev Biol. 2019 May 30. pii: S1084-9521(18)30169-1. [Epub ahead of print]

Autophagy and mitophagy in cancer metabolic remodelling.

Fabio Ferro, Stéphane Servais, Pierre Besson, Sébastien Roger, Jean-François Dumas, Lucie Brisson.

  Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global metabolic adaptations allowing them to survive in the low oxygen and nutrient tumour microenvironment. Among these metabolic adaptations, cancer cells use glycolysis but also mitochondrial oxidations to produce ATP and building blocks needed for their high proliferation rate. Another particular adaptation of cancer cell metabolism is the use of autophagy and specific forms of autophagy like mitophagy to recycle intracellular components in condition of metabolic stress or during anticancer treatments. The plasticity of cancer cell metabolism is a major limitation of anticancer treatments and could participate to therapy resistances. The aim of this review is to report recent advances in the understanding of the relationship between tumour metabolism and autophagy/mitophagy in order to propose new therapeutic strategies.

Keywords:  Cancer metabolism; ROS; autophagy; ion channel; mitochondria; mitophagy

DOI:  https://doi.org/10.1016/j.semcdb.2019.05.029
Cell Metab. 2019 May 14. pii: S1550-4131(19)30246-3. [Epub ahead of print]

Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes.

Cristina Aguayo-Mazzucato, Joshua Andle, Terrence B Lee, Ayush Midha, Lindsay Talemal, Vaja Chipashvili, Jennifer Hollister-Lock, Jan van Deursen, Gordon Weir, Susan Bonner-Weir.

  Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged β cells resemble those preceding the development of diabetes, the contribution of β cell aging and senescence remains unclear. We generated a β cell senescence signature and found that insulin resistance accelerates β cell senescence leading to loss of function and cellular identity and worsening metabolic profile. Senolysis (removal of senescent cells), using either a transgenic INK-ATTAC model or oral ABT263, improved glucose metabolism and β cell function while decreasing expression of markers of aging, senescence, and senescence-associated secretory profile (SASP). Beneficial effects of senolysis were observed in an aging model as well as with insulin resistance induced both pharmacologically (S961) and physiologically (high-fat diet). Human senescent β cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of β cells as a preventive and alleviating strategy for T2D.

Keywords:  SASP; beta cells; glucose metabolism; insulin resistance; insulin secretion; senescence; senescence signature; senescence-associated secretory profile; senolytic therapies; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2019.05.006
Nat Commun. 2019 Jun 03. 10(1): 2387

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition.

Branca I Pereira, Oliver P Devine, Milica Vukmanovic-Stejic, Emma S Chambers, Priya Subramanian, Neil Patel, Alex Virasami, Neil J Sebire, Veronica Kinsler, Alexis Valdovinos, Claude Jourdan LeSaux, João F Passos, Antony Antoniou, Malcom H A Rustin, Judith Campisi, Arne N Akbar.

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.

DOI: https://doi.org/10.1038/s41467-019-10335-5
Semin Cell Dev Biol. 2019 May 30. pii: S1084-9521(18)30187-3. [Epub ahead of print]

Mitochondria as playmakers of apoptosis, autophagy and senescence.

Marianna Abate, Agostino Festa, Michela Falco, Angela Lombardi, Amalia Luce, Anna Grimaldi, Silvia Zappavigna, Pasquale Sperlongano, Carlo Irace, Michele Caraglia, Gabriella Misso.

  Mitochondria are the key energy-producing organelles and cellular source of reactive species. They are responsible for managing cell life and death by a balanced homeostasis passing through a network of structures, regulated principally via fission and fusion. Herein we discuss about the most advanced findings considering mitochondria as dynamic biophysical systems playing compelling roles in the regulation of energy metabolism in both physiologic and pathologic processes controlling cell death and survival. Precisely, we focus on the mitochondrial commitment to the onset, maintenance and counteraction of apoptosis, autophagy and senescence in the bioenergetic reprogramming of cancer cells. In this context, looking for a pharmacological manipulation of cell death processes as a successful route for future targeted therapies, there is major biotechnological challenge in underlining the location, function and molecular mechanism of mitochondrial proteins. Based on the critical role of mitochondrial functions for cellular health, a better knowledge of the main molecular players in mitochondria disfunction could be decisive for the therapeutical control of degenerative diseases, including cancer.

Keywords:  apoptosis; autophagy; cancer; metabolism; mitochondrion; senescence

DOI:  https://doi.org/10.1016/j.semcdb.2019.05.022