bims-apauto 2021-04-25 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2021–04–25
nine papers selected by
Su Hyun Lee, Seoul National University

Selectivity of mRNA degradation by autophagy in yeast.
Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology.
Resveratrol induces AMPK and mTOR signaling inhibition-mediated autophagy and apoptosis in multiple myeloma cells.
Interplay of autophagy and cancer stem cells in hepatocellular carcinoma.
Ferroptosis: Biochemistry and Biology in Cancers.
Bidirectional interconversion between PtdIns4P and PtdIns(4,5)P2 is required for autophagic lysosome reformation and protection from skeletal muscle disease.
MCOLN1/TRPML1 finely controls oncogenic autophagy in cancer by mediating zinc influx.
HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons.
Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy.

Nat Commun. 2021 Apr 19. 12(1): 2316

Selectivity of mRNA degradation by autophagy in yeast.

Shiho Makino, Tomoko Kawamata, Shintaro Iwasaki, Yoshinori Ohsumi.

Synthesis and degradation of cellular constituents must be balanced to maintain cellular homeostasis, especially during adaptation to environmental stress. The role of autophagy in the degradation of proteins and organelles is well-characterized. However, autophagy-mediated RNA degradation in response to stress and the potential preference of specific RNAs to undergo autophagy-mediated degradation have not been examined. In this study, we demonstrate selective mRNA degradation by rapamycin-induced autophagy in yeast. Profiling of mRNAs from the vacuole reveals that subsets of mRNAs, such as those encoding amino acid biosynthesis and ribosomal proteins, are preferentially delivered to the vacuole by autophagy for degradation. We also reveal that autophagy-mediated mRNA degradation is tightly coupled with translation by ribosomes. Genome-wide ribosome profiling suggested a high correspondence between ribosome association and targeting to the vacuole. We propose that autophagy-mediated mRNA degradation is a unique and previously-unappreciated function of autophagy that affords post-transcriptional gene regulation.

DOI: https://doi.org/10.1038/s41467-021-22574-6
Biomol Ther (Seoul). 2021 Apr 20.

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology.

McNeil Valencia, Sung Rae Kim, Yeseul Jang, Sung Hoon Lee.

  Autophagy is an important degradative pathway that eliminates misfolded proteins and damaged organelles from cells. Autophagy is crucial for neuronal homeostasis and function. A lack of or deficiency in autophagy leads to the accumulation of protein aggregates, which are associated with several neurodegenerative diseases. Compared with non-neuronal cells, neurons exhibit rapid autophagic flux because damaged organelles or protein aggregates cannot be diluted in post-mitotic cells; because of this, these cells exhibit characteristic features of autophagy, such as compartment-specific autophagy, which depends on polarized structures and rapid autophagy flux. In addition, neurons exhibit compartment-specific autophagy, which depends on polarized structures. Neuronal autophagy may have additional physiological roles other than amino acid recycling. In this review, we focus on the characteristics and regulatory factors of neuronal autophagy. We also describe intracellular selective autophagy in neurons and its association with neurodegenerative diseases.

Keywords:  Autophagy; Characteristic; Neurological disorder; Neurons; Selective autophagy

DOI:  https://doi.org/10.4062/biomolther.2021.012
Acta Biochim Biophys Sin (Shanghai). 2021 Apr 23. pii: gmab042. [Epub ahead of print]

Resveratrol induces AMPK and mTOR signaling inhibition-mediated autophagy and apoptosis in multiple myeloma cells.

Ruye Ma, Dandan Yu, Yu Peng, Hongfei Yi, Yingcong Wang, Taofang Cheng, Bingqing Shi, Guang Yang, Weiming Lai, Xiaosong Wu, Ye Lu, Jumei Shi.

  Resveratrol, a natural compound extracted from the skins of grapes, berries, or other fruits, has been shown to have anti-tumor effects against multiple myeloma (MM) via promoting apoptosis and inhibiting cell viability. In addition to apoptosis, autophagy also plays a significant role in anti-tumor effects. However, whether autophagy is involved in anti-MM activity of resveratrol remains unclear. In this study, human MM cell lines U266, RPMI-8226, and NCI-H929 were treated with resveratrol. Cell Counting Kit-8 assay and colony formation assay were used to measure cell viability. Western blot analysis was used to detect apoptosis- and autophagy-associated proteins. 3-Methyladenine (3-MA) was applied to inhibit autophagy. Results showed that resveratrol inhibited cell viability and colony formation via promoting apoptosis and autophagy in MM cell lines U266, RPMI-8226, and NCI-H929. Resveratrol promoted apoptosis-related proteins, Caspase-3 activating poly-ADP-ribose polymerase and Caspase-3 cleavage, and decreased the protein level of Survivin in a dose-dependent manner. Additionally, resveratrol upregulated the levels of LC3 and Beclin1 in a dose-dependent way, indicating that autophagy might be implicated in anti-MM effect of resveratrol. Furthermore, 3-MA relieved the cytotoxicity of resveratrol by blocking the autophagic flux. Resveratrol increased the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and decreased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream substrates p70S6K and 4EBP1 in a dose-dependent manner, leading to autophagy. Therefore, our results suggest that resveratrol exerts anti-MM effects through apoptosis and autophagy, which can be used as a new therapeutic strategy for MM in clinic.

Keywords:  AMP-activated protein kinase; apoptosis; autophagy; multiple myeloma; resveratrol

DOI:  https://doi.org/10.1093/abbs/gmab042
Mol Biol Rep. 2021 Apr 24.

Interplay of autophagy and cancer stem cells in hepatocellular carcinoma.

Magdelyn Mei-Theng Wong, Hui-Yin Chan, Norazlin Abdul Aziz, Thamil Selvee Ramasamy, Jan-Jin Bong, Ewe Seng Ch'ng, Subasri Armon, Suat-Cheng Peh, Sin-Yeang Teow.

  Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.

Keywords:  Autophagy; Cancer stem cells; Hepatocellular carcinoma; Liver cancer; Sirtuin 1; Suppression; Tumour progression

DOI:  https://doi.org/10.1007/s11033-021-06334-9
Front Oncol. 2021 ;11 579286

Ferroptosis: Biochemistry and Biology in Cancers.

Zhiyuan Shi, Lei Zhang, Jianzhong Zheng, Huimin Sun, Chen Shao.

  The challenge of eradicating cancer is that cancer cells possess diverse mechanisms to protect themselves from clinical strategies. Recently, ferroptosis has been shown to exhibit appreciable anti-tumor activity that could be harnessed for cancer therapy in the future. Ferroptosis is an iron-dependent form of regulated cell death that is characterized by the oxidization of polyunsaturated fatty acids (PUFAs) and accumulation of lipid peroxides. Ferroptosis has been closely correlated with numerous biological processes, such as amino acid metabolism, glutathione metabolism, iron metabolism, and lipid metabolism, as well as key regulators including GPX4, FSP1, NRF2, and p53. Although ferroptosis could be involved in killing various cancer cells, multiple aspects of this phenomenon remain unresolved. In this review, we summarize the biochemistry and biology of ferroptosis in diverse cancers and discuss the potential mechanisms of ferroptosis, which might pave the way for guiding cancer therapeutics.

Keywords:  amino acid metabolism; cancers; ferroptosis; iron metabolism; lipid metabolism

DOI:  https://doi.org/10.3389/fonc.2021.579286
Autophagy. 2021 Apr 20. 1-3

Bidirectional interconversion between PtdIns4P and PtdIns(4,5)P2 is required for autophagic lysosome reformation and protection from skeletal muscle disease.

Matthew J Eramo, Rajendra Gurung, Christina A Mitchell, Meagan J McGrath.

  Autophagic lysosome reformation (ALR) recycles autolysosome membranes formed during autophagy, to make lysosomes and is essential for continued autophagy function. Localized membrane remodeling on autolysosomes leads to the extension of reformation tubules, which undergo scission to form new lysosomes. The phosphoinositides phosphatidylinositol-4-phosphate (PtdIns4P) and phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P2) induce this remodeling by recruiting protein effectors to membranes. We identified the inositol polyphosphate 5-phosphatase INPP5K, which converts PtdIns(4,5)P2 to PtdIns4P is essential for ALR in skeletal muscle. INPP5K mutations that reduce its 5-phosphatase activity are known to cause muscular dystrophy, via an undefined mechanism. We generated skeletal muscle-specific inpp5k knockout mice which exhibited severe muscle disease, with lysosome depletion and marked autophagy inhibition. This was due to decreased PtdIns4P and increased PtdIns(4,5)P2 on autolysosomes, causing reduced scission of reformation tubules. ALR was restored in cells with loss of INPP5K by expression of wild-type INPP5K, but not muscle-disease causing mutants. Therefore on autolysosomes, both PtdIns(4,5)P2 generation and its removal by INPP5K is required for completion of ALR. Furthermore, skeletal muscle shows a dependence on the membrane recycling ALR pathway to maintain lysosome homeostasis and ensure the protective role of autophagy against disease.

Keywords:  Autophagic lysosome reformation; INPP5K; PtdIns(4, 5)P2; PtdIns4P; autophagy; inositol polyphosphate 5-phosphatase; lysosome; muscular dystrophy; phosphoinositide; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2021.1916195
Autophagy. 2021 Apr 23. 1-22

MCOLN1/TRPML1 finely controls oncogenic autophagy in cancer by mediating zinc influx.

Jiansong Qi, Yanhong Xing, Yucheng Liu, Meng-Meng Wang, Xiangqing Wei, Zhongheng Sui, Lin Ding, Yang Zhang, Chen Lu, Yuan-Hui Fei, Nan Liu, Rong Chen, Mengmei Wu, Lijuan Wang, Zhenyu Zhong, Ting Wang, Yifan Liu, Yuqing Wang, Jiamei Liu, Haoxing Xu, Feng Guo, Wuyang Wang.

  Macroautophagy/autophagy is elevated to ensure the high demand for nutrients for the growth of cancer cells. Here we demonstrated that MCOLN1/TRPML1 is a pharmaceutical target of oncogenic autophagy in cancers such as pancreatic cancer, breast cancer, gastric cancer, malignant melanoma, and glioma. First, we showed that activating MCOLN1, by increasing expression of the channel or using the MCOLN1 agonists, ML-SA5 or MK6-83, arrests autophagic flux by perturbing fusion between autophagosomes and lysosomes. Second, we demonstrated that MCOLN1 regulates autophagy by mediating the release of zinc from the lysosome to the cytosol. Third, we uncovered that zinc influx through MCOLN1 blocks the interaction between STX17 (syntaxin 17) in the autophagosome and VAMP8 in the lysosome and thereby disrupting the fusion process that is determined by the two SNARE proteins. Furthermore, we demonstrated that zinc influx originating from the extracellular fluid arrests autophagy by the same mechanism as lysosomal zinc, confirming the fundamental function of zinc as a participant in membrane trafficking. Last, we revealed that activating MCOLN1 with the agonists, ML-SA5 or MK6-83, triggers cell death of a number of cancer cells by evoking autophagic arrest and subsequent apoptotic response and cell cycle arrest, with little or no effect observed on normal cells. Consistent with the in vitro results, administration of ML-SA5 in Patu 8988 t xenograft mice profoundly suppresses tumor growth and improves survival. These results establish that a lysosomal cation channel, MCOLN1, finely controls oncogenic autophagy in cancer by mediating zinc influx into the cytosol.

Keywords:  Autophagic arrest; MCOLN1; autophagosome-lysosome fusion; cancer; zinc influx

DOI:  https://doi.org/10.1080/15548627.2021.1917132
Autophagy. 2021 Apr 23. 1-15

HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons.

Maryline Santerre, Sterling P Arjona, Charles Ns Allen, Shannon Callen, Shilpa Buch, Bassel E Sawaya.

  Despite the promising therapeutic effects of combinatory antiretroviral therapy (cART), 20% to 30% of HIV/AIDS patients living with long term infection still exhibit related cognitive and motor disorders. Clinical studies in HIV-infected patients revealed evidence of basal ganglia dysfunction, tremors, fine motor movement deficits, gait, balance, and increased risk of falls. Among older HIV+ adults, the frequency of cases with SNCA/α-synuclein staining is higher than in older healthy persons and may predict an increased risk of developing a neurodegenerative disease. The accumulation of SNCA aggregates known as Lewy Bodies is widely described to be directly linked to motor dysfunction. These aggregates are naturally removed by Macroautophagy/autophagy, a cellular housekeeping mechanism, that can be disturbed by HIV-1. The molecular mechanisms involved in linking HIV-1 proteins and autophagy remain mostly unclear and necessitates further exploration. We showed that HIV-1 Vpr protein triggers the accumulation of SNCA in neurons after decreasing lysosomal acidification, deregulating lysosome positioning, and the expression levels of several proteins involved in lysosomal maturation. Viruses and retroviruses such as HIV-1 are known to manipulate autophagy in order to use it for their replication while blocking the degradative final step, which could destroy the virus itself. Our study highlights how the suppression of neuronal autophagy by HIV-1 Vpr is a mechanism leading to toxic protein aggregation and neurodegeneration.

Keywords:  Alpha-synuclein; HIV-1; Snapin; autophagy; lysosomes; motor dysfunction; neurons

DOI:  https://doi.org/10.1080/15548627.2021.1915641
J Cell Biol. 2021 Jun 07. pii: e202006128. [Epub ahead of print]220(6):

Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy.

Thaddaeus Mutugi Nthiga, Birendra Kumar Shrestha, Jack-Ansgar Bruun, Kenneth Bowitz Larsen, Trond Lamark, Terje Johansen.

The Golgi complex is essential for the processing, sorting, and trafficking of newly synthesized proteins and lipids. Golgi turnover is regulated to meet different cellular physiological demands. The role of autophagy in the turnover of Golgi, however, has not been clarified. Here we show that CALCOCO1 binds the Golgi-resident palmitoyltransferase ZDHHC17 to facilitate Golgi degradation by autophagy during starvation. Depletion of CALCOCO1 in cells causes expansion of the Golgi and accumulation of its structural and membrane proteins. ZDHHC17 itself is degraded by autophagy together with other Golgi membrane proteins such as TMEM165. Taken together, our data suggest a model in which CALCOCO1 mediates selective Golgiphagy to control Golgi size and morphology in eukaryotic cells via its interaction with ZDHHC17.

DOI: https://doi.org/10.1083/jcb.202006128