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Selective autophagy

Jorge Moscat, Michael Karin, Maria T Diaz-Meco
Adaptor proteins participate in selective autophagy, which is critical for cellular detoxification and stress relief. However, new evidence supports an autophagy-independent key role of the adaptor p62 (encoded by the gene Sqstm1) in signaling functions central to tumor initiation in the epithelium and suppression of tumor progression in the stroma.
October 20, 2016: Cell
Raffaela Torggler, Daniel Papinski, Thorsten Brach, Levent Bas, Martina Schuschnig, Thaddäus Pfaffenwimmer, Sabrina Rohringer, Tamara Matzhold, David Schweida, Andrea Brezovich, Claudine Kraft
Autophagy is a potent cellular degradation pathway, and its activation needs to be tightly controlled. Cargo receptors mediate selectivity during autophagy by bringing cargo to the scaffold protein Atg11 and, in turn, to the autophagic machinery, including the central autophagy kinase Atg1. Here we show how selective autophagy is tightly regulated in space and time to prevent aberrant Atg1 kinase activation and autophagy induction. We established an induced bypass approach (iPass) that combines genetic deletion with chemically induced dimerization to evaluate the roles of Atg13 and cargo receptors in Atg1 kinase activation and selective autophagy progression...
October 20, 2016: Molecular Cell
Ariadne Vlahakis, Jayanta Debnath
In this issue of Molecular Cell, Torggler et al. (2016) leverage innovative synthetic biology approaches to dissect the spatiotemporal activation of Atg1 kinase during selective autophagy, revealing two distinct pathways that coordinately initiate autophagosome formation at the yeast vacuole.
October 20, 2016: Molecular Cell
Xin-Shuang Yu, Juan Du, Yu-Jun Fan, Feng-Jun Liu, Li-Li Cao, Ning Liang, De-Guo Xu, Jian-Dong Zhang
OBJECTIVE: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. RESULTS: The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h...
October 18, 2016: Oncotarget
Ya-Qin Tan, Jing Zhang, Gang Zhou
Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression...
October 20, 2016: Autophagy
Zuriñe Antón, Ane Landajuela, Javier H Hervás, L Ruth Montes, Sonia Hernández-Tiedra, Guillermo Velasco, Felix M Goñi, Alicia Alonso
The phospholipid cardiolipin (CL) has been proposed to play a role in selective mitochondrial autophagy, or mitophagy. CL externalization to the outer mitochondrial membrane would act as a signal for the human Atg8 ortholog subfamily, MAP1LC3 (LC3). The latter would mediate both mitochondrial recognition and autophagosome formation, ultimately leading to removal of damaged mitochondria. We have applied quantitative biophysical techniques to the study of CL interaction with various Atg8 human orthologs, namely LC3B, GABARAPL2 and GABARAP...
October 20, 2016: Autophagy
K R Vogel, G R Ainslie, E E W Jansen, G S Salomons, K M Gibson
Aldehyde dehydrogenase 5a1-deficient (aldh5a1(-/-)) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1(-/-) mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR...
October 16, 2016: Biochimica et Biophysica Acta
Florian Rouaud, Jean-Luc Boucher, Anny Slama-Schwok, Stéphane Rocchi
Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment...
October 14, 2016: Oncotarget
Barbara Kathage, Sebastian Gehlert, Anna Ulbricht, Laura Lüdecke, Victor E Tapia, Zacharias Orfanos, Daniela Wenzel, Wilhelm Bloch, Rudolf Volkmer, Bernd K Fleischmann, Dieter O Fürst, Jörg Höhfeld
The cochaperone BAG3 is a central protein homeostasis factor in mechanically strained mammalian cells. It mediates the degradation of unfolded and damaged forms of the actin-crosslinker filamin through chaperone-assisted selective autophagy (CASA). In addition, BAG3 stimulates filamin transcription in order to compensate autophagic disposal and to maintain the actin cytoskeleton under strain. Here we demonstrate that BAG3 coordinates protein synthesis and autophagy through spatial regulation of the mammalian target of rapamycin complex 1 (mTORC1)...
October 15, 2016: Biochimica et Biophysica Acta
Chrisovalantis Papadopoulos, Philipp Kirchner, Monika Bug, Daniel Grum, Lisa Koerver, Nina Schulze, Robert Poehler, Alina Dressler, Sven Fengler, Khalid Arhzaouy, Vanda Lux, Michael Ehrmann, Conrad C Weihl, Hemmo Meyer
Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation...
October 17, 2016: EMBO Journal
Fiorenza Fumagalli, Julia Noack, Timothy J Bergmann, Eduardo Cebollero Presmanes, Giorgia Brambilla Pisoni, Elisa Fasana, Ilaria Fregno, Carmela Galli, Marisa Loi, Tatiana Soldà, Rocco D'Antuono, Andrea Raimondi, Martin Jung, Armin Melnyk, Stefan Schorr, Anne Schreiber, Luca Simonelli, Luca Varani, Caroline Wilson-Zbinden, Oliver Zerbe, Kay Hofmann, Matthias Peter, Manfredo Quadroni, Richard Zimmermann, Maurizio Molinari
The endoplasmic reticulum (ER) is a site of protein biogenesis in eukaryotic cells. Perturbing ER homeostasis activates stress programs collectively called the unfolded protein response (UPR). The UPR enhances production of ER-resident chaperones and enzymes to reduce the burden of misfolded proteins. On resolution of ER stress, ill-defined, selective autophagic programs remove excess ER components. Here we identify Sec62, a constituent of the translocon complex regulating protein import in the mammalian ER, as an ER-resident autophagy receptor...
October 17, 2016: Nature Cell Biology
Zeng Xiaowei, Liu Cuicui, Han Ning, Bian Hongwu, Zhu Muyuan
Autophagy is an evolutionarily highly conserved catabolic pathway among eukaryotic cells that protects the organisms against environmental stress. Normally, autophagy is mainly involved with autophagy-related proteins(ATGs) and autophagic regulators including a series of cytoplasmic proteins and small molecules. Besides, the selective autophagy, which targets damaged organalles or protein aggregates, is mediated by the additional receptors to help the ATGs recognize different substrates. In this review, we summarize recent advances in autophagic regulators like ROS(Reactive oxygen species), TOR(Target of rapamycin) and receptors like NBR1(Neighbor of BRCA1 gene protein), RPN10(Regulatory particle non-ATPase 10) as well as their functional mechanisms mainly in Arabidopsis thaliana...
July 20, 2016: Yi Chuan, Hereditas
Leiming Li, Yan Li, Jiansong Zhao, Shuli Fan, Liguo Wang, Xu Li
Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines...
2016: OncoTargets and Therapy
Mingsheng Zhang, Enda Xue, Wei Shao
BACKGROUND: Nephroblastoma (Wilms' tumor [WT]) is the most common malignant renal cancer in children. Although the outcome of WT has significantly improved as a result of the combination of surgery, chemotherapy, and radiotherapy; in some cases WT results in severe complications. Thus, novel strategies that would decrease treatment burden are required. The aim of the current study was to investigate the synergistic antitumor effect of andrographolide (AND) in combination with vincristine (VCR) on WT cells...
2016: Drug Design, Development and Therapy
Milana Fraiberg, Zvulun Elazar
Selective autophagy, an essential process for maintaining intracellular homeostasis, depends on precise target recognition and local activation. Reporting in Developmental Cell, Chauhan et al. (2016) elegantly demonstrate that interaction between TRIM16 and Galectin3 orchestrates the recruitment of core autophagic factors and activates selective autophagy at the site of damaged endomembranes.
October 10, 2016: Developmental Cell
Hao Zhang, Weipeng Su, Zhixiong Ying, Yueping Chen, Le Zhou, Yue Li, Jingfei Zhang, Lili Zhang, Tian Wang
PURPOSE: The objective of the present study was to test the hypothesis that N-acetylcysteine (NAC) may play beneficial roles against intrauterine growth retardation (IUGR)-induced hepatic damage in suckling piglets. METHODS: Fourteen IUGR and seven normal birth weight (NBW) neonatal male piglets were selected. Piglets were weaned at 7 days of postnatal age and fed the control formula milk (NBW-CON and IUGR-CON groups) or the control formula milk supplemented with 1...
October 8, 2016: European Journal of Nutrition
Thomas G McWilliams, Ian G Ganley
The past decade has seen an intensive and concerted research effort into the molecular regulation of mitophagy, the selective autophagy of mitochondria. Cell-based studies have implicated mitophagy in the pathology of diverse conditions ranging from cancer to neurodegeneration. However, a definitive link between mitophagy and the aetiology of human disease remains to be demonstrated. Moreover, we do not know how pervasive mammalian mitophagy is in vivo and fundamental questions remain unanswered. For example, is mitophagy common to all tissues under basal conditions or does it only occur in highly oxidative tissues under stress? This paucity of knowledge is largely due to a lack of experimentally tractable tools that can measure and monitor mitophagy in tissues...
October 7, 2016: Autophagy
Ki Won Lee, Hyung Won Ryu, Sang-Seok Oh, Soojong Park, Hamadi Madhi, Jiyun Yoo, Ki-Hun Park, Kwang Dong Kim
Melanogenesis is a key pathway for the regulation of skin pigmentation and the development of skin-lightening/whitening drugs or cosmetics. In this study, we found that β-mangostin from seedcases of Garcinia mangostana inhibited α-melanocyte-stimulating hormone (α-MSH)-mediated melanogenesis in B16F10 melanoma cells and a three-dimensional human skin model. β-Mangostin significantly inhibited the protein level of tyrosinase induced by α-MSH in UPS (ubiquitin proteasome system)-independent and lysosome-dependent manner...
October 7, 2016: Experimental Dermatology
Jingli Hao, Peter Graham, Lei Chang, Jie Ni, Valerie Wasinger, Julia Beretov, Junli Deng, Wei Duan, Joseph Bucci, David Malouf, David Gillatt, Yong Li
Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry...
September 30, 2016: Oncotarget
Meeta Pathak, O K Olstad, Liv Drolsum, Morten C Moe, Natalia Smorodinova, Sarka Kalasova, Katerina Jirsova, Bjørn Nicolaissen, Agate Noer
Patients with limbal stem cell deficiency (LSCD) often experience pain and photophobia due to recurrent epithelial defects and chronic inflammation of the cornea. Successfully restoring a healthy corneal surface in these patients by transplantation of ex vivo expanded human limbal epithelial cells (LECs) may alleviate these symptoms and significantly improve their quality of life. The clinical outcome of transplantation is known to be influenced by the quality of transplanted cells. Presently, several different protocols for cultivation and transplantation of LECs are in use...
October 1, 2016: Experimental Eye Research
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