bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2019–05–05
eight papers selected by
Viktor Korolchuk, Newcastle University
  1. Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins.
  2. STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism.
  3. ATL3, a cargo receptor for reticulophagy.
  4. The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1 localization and activity.
  5. TORC1 specifically inhibits microautophagy through ESCRT-0.
  6. Identification of Kinases Responsible for p53-Dependent Autophagy.
  7. A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy.
  8. Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans.
  1. Nat Commun. 2019 May 03. 10(1): 2055
    Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins.
    Martina Wirth, Wenxin Zhang, Minoo Razi, Lynet Nyoni, Dhira Joshi, Nicola O'Reilly, Terje Johansen, Sharon A Tooze, Stéphane Mouilleron.
      Autophagy is an essential recycling and quality control pathway. Mammalian ATG8 proteins drive autophagosome formation and selective removal of protein aggregates and organelles by recruiting autophagy receptors and adaptors that contain a LC3-interacting region (LIR) motif. LIR motifs can be highly selective for ATG8 subfamily proteins (LC3s/GABARAPs), however the molecular determinants regulating these selective interactions remain elusive. Here we show that residues within the core LIR motif and adjacent C-terminal region as well as ATG8 subfamily-specific residues in the LIR docking site are critical for binding of receptors and adaptors to GABARAPs. Moreover, rendering GABARAP more LC3B-like impairs autophagy receptor degradation. Modulating LIR binding specificity of the centriolar satellite protein PCM1, implicated in autophagy and centrosomal function, alters its dynamics in cells. Our data provides new mechanistic insight into how selective binding of LIR motifs to GABARAPs is achieved, and elucidate the overlapping and distinct functions of ATG8 subfamily proteins.
    DOI:  https://doi.org/10.1038/s41467-019-10059-6
  2. Nat Commun. 2019 May 03. 10(1): 2059
    STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism.
    Hongxu Xian, Qiaoyun Yang, Lin Xiao, Han-Ming Shen, Yih-Cherng Liou.
      Mitophagy is the selective autophagic targeting and removal of dysfunctional mitochondria. While PINK1/Parkin-dependent mitophagy is well-characterized, PINK1/Parkin-independent route is poorly understood. Using structure illumination microscopy (SR-SIM), we demonstrate that the SNARE protein Syntaxin 17 (STX17) initiates mitophagy upon depletion of outer mitochondrial membrane protein Fis1. With proteomics analysis, we identify the STX17-Fis1 interaction, which controls the dynamic shuffling of STX17 between ER and mitochondria. Fis1 loss results in aberrant STX17 accumulation on mitochondria, which exposes the N terminus and promotes self-oligomerization to trigger mitophagy. Mitochondrial STX17 interacts with ATG14 and recruits core autophagy proteins to form mitophagosome, followed by Rab7-dependent mitophagosome-lysosome fusion. Furthermore, Fis1 loss impairs mitochondrial respiration and potentially sensitizes cells to mitochondrial clearance, which is mediated through canonical autophagy machinery, closely linking non-selective macroautophagy to mitochondrial turnover. Our findings uncover a PINK1/Parkin-independent mitophagic mechanism in which outer mitochondrial membrane protein Fis1 regulates mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41467-019-10096-1
  3. Autophagy. 2019 Apr 28. 1-2
    ATL3, a cargo receptor for reticulophagy.
    Qingzhou Chen, Junlin Teng, Jianguo Chen.
      The endoplasmic reticulum (ER) is the largest membranous organelle, and its turnover ensures cellular homeostasis. The selective macroautophagy/autophagy of the ER (reticulophagy) guarantees the balance of ER turnover. However, the mechanism and physiological relevance of reticulophagy is largely unknown. Recently, we identified ATL3 (atlastin GTPase 3), generally considered to mediate ER fusion, as a receptor for reticulophagy. ATL3 specifically interacts with the GABARAP subfamily proteins of the Atg8-family, and this association is crucial for ATL3's role as a receptor for reticulophagy. Moreover, 2 hereditary sensory and autonomic neuropathies type 1 (HSANI)-associated mutations of ATL3 (Tyr192Cys and Pro338Arg) impair ATL3's binding to GABARAP and function in reticulophagy. Therefore, we illuminate a new function of ATL3 in reticulophagy and the potential physiological relevance of reticulophagy in neurodegenerative diseases.
    Keywords:  ATL3; GABARAP; hereditary sensory and autonomic neuropathies type 1 (HSANI); reticulophagy receptors; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2019.1609862
  4. Nat Cell Biol. 2019 May;21(5): 614-626
    The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1 localization and activity.
    Lin Gan, Akiko Seki, Kimberle Shen, Harini Iyer, Kyuho Han, Arnold Hayer, Roy Wollman, Xuecai Ge, Jerry R Lin, Gautam Dey, William S Talbot, Tobias Meyer.
      Cell growth is controlled by a lysosomal signalling complex containing Rag small GTPases and mammalian target of rapamycin complex 1 (mTORC1) kinase. Here, we carried out a microscopy-based genome-wide human short interfering RNA screen and discovered a lysosome-localized G protein-coupled receptor (GPCR)-like protein, GPR137B, that interacts with Rag GTPases, increases Rag localization and activity, and thereby regulates mTORC1 translocation and activity. High GPR137B expression can recruit and activate mTORC1 in the absence of amino acids. Furthermore, GPR137B also regulates the dissociation of activated Rag from lysosomes, suggesting that GPR137B controls a cycle of Rag activation and dissociation from lysosomes. GPR137B-knockout cells exhibited defective autophagy and an expanded lysosome compartment, similar to Rag-knockout cells. Like zebrafish RagA mutants, GPR137B-mutant zebrafish had upregulated TFEB target gene expression and an expanded lysosome compartment in microglia. Thus, GPR137B is a GPCR-like lysosomal regulatory protein that controls dynamic Rag and mTORC1 localization and activity as well as lysosome morphology.
    DOI:  https://doi.org/10.1038/s41556-019-0321-6
  5. Curr Genet. 2019 Apr 30.
    TORC1 specifically inhibits microautophagy through ESCRT-0.
    Riko Hatakeyama, Claudio De Virgilio.
      Nutrient starvation induces the degradation of specific plasma membrane proteins through the multivesicular body (MVB) sorting pathway and of vacuolar membrane proteins through microautophagy. Both of these processes require the gateway protein Vps27, which recognizes ubiquitinated cargo proteins at phosphatidylinositol 3-phosphate-rich membranes as part of a heterodimeric complex coined endosomal sorting complex required for transport 0. The target of rapamycin complex 1 (TORC1), a nutrient-activated central regulator of cell growth, directly phosphorylates Vps27 to antagonize its function in microautophagy, but whether this also serves to restrain MVB sorting at endosomes is still an open question. Here, we show that TORC1 inhibits both the MVB pathway-driven turnover of the plasma membrane-resident high-affinity methionine permease Mup1 and the inositol transporter Itr1 and the microautophagy-dependent degradation of the vacuolar membrane-associated v-ATPase subunit Vph1. Using a Vps277D variant that mimics the TORC1-phosphorylated state of Vps27, we further show that cargo sorting of Vph1 at the vacuolar membrane, but not of Mup1 and Itr1 at endosomes, is sensitive to the TORC1-controlled modifications of Vps27. Thus, TORC1 specifically modulates microautophagy through phosphorylation of Vps27, but controls MVB sorting through alternative mechanisms.
    Keywords:  Endosomal sorting complex required for transport (ESCRT); Microautophagy; Multivesicular body; Target of rapamycin complex 1 (TORC1); Vps27
    DOI:  https://doi.org/10.1007/s00294-019-00982-y
  6. iScience. 2019 Apr 23. pii: S2589-0042(19)30120-8. [Epub ahead of print]15 109-118
    Identification of Kinases Responsible for p53-Dependent Autophagy.
    Stephanie L Celano, Lisette P Yco, Matthew G Kortus, Abigail R Solitro, Hakan Gunaydin, Mark Scott, Edward Spooner, Ronan C O'Hagan, Peter Fuller, Katie R Martin, Stuart D Shumway, Jeffrey P MacKeigan.
      In cancer, autophagy is upregulated to promote cell survival and tumor growth during times of nutrient stress and can confer resistance to drug treatments. Several major signaling networks control autophagy induction, including the p53 tumor suppressor pathway. In response to DNA damage and other cellular stresses, p53 is stabilized and activated, while HDM2 binds to and ubiquitinates p53 for proteasome degradation. Thus blocking the HDM2-p53 interaction is a promising therapeutic strategy in cancer; however, the potential survival advantage conferred by autophagy induction may limit therapeutic efficacy. In this study, we leveraged an HDM2 inhibitor to identify kinases required for p53-dependent autophagy. Interestingly, we discovered that p53-dependent autophagy requires several kinases, including the myotonic dystrophy protein kinase-like alpha (MRCKα). MRCKα is a CDC42 effector reported to activate actin-myosin cytoskeletal reorganization. Overall, this study provides evidence linking MRCKα to autophagy and reveals additional insights into the role of kinases in p53-dependent autophagy.
    Keywords:  Biological Sciences; Cell Biology; Functional Aspects of Cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2019.04.023
  7. Nat Commun. 2019 04 29. 10(1): 1973
    A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy.
    Qiyao Chai, Xudong Wang, Lihua Qiang, Yong Zhang, Pupu Ge, Zhe Lu, Yanzhao Zhong, Bingxi Li, Jing Wang, Lingqiang Zhang, Dawang Zhou, Wei Li, Wenzhu Dong, Yu Pang, George Fu Gao, Cui Hua Liu.
      Ubiquitin-mediated xenophagy, a type of selective autophagy, plays crucial roles in host defense against intracellular pathogens including Mycobacterium tuberculosis (Mtb). However, the exact mechanism by which host ubiquitin targets invaded microbes to trigger xenophagy remains obscure. Here we show that ubiquitin could recognize Mtb surface protein Rv1468c, a previously unidentified ubiquitin-binding protein containing a eukaryotic-like ubiquitin-associated (UBA) domain. The UBA-mediated direct binding of ubiquitin to, but not E3 ubiquitin ligases-mediated ubiquitination of, Rv1468c recruits autophagy receptor p62 to deliver mycobacteria into LC3-associated autophagosomes. Disruption of Rv1468c-ubiquitin interaction attenuates xenophagic clearance of Mtb in macrophages, and increases bacterial loads in mice with elevated inflammatory responses. Together, our findings reveal a unique mechanism of host xenophagy triggered by direct binding of ubiquitin to the pathogen surface protein, and indicate a diplomatic strategy adopted by Mtb to benefit its persistent intracellular infection through controlling intracellular bacterial loads and restricting host inflammatory responses.
    DOI:  https://doi.org/10.1038/s41467-019-09955-8
  8. Elife. 2019 May 03. pii: e43059. [Epub ahead of print]8
    Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans.
    Chaolie Huang, Sara Wagner-Valladolid, Amberley D Stephens, Raimund Jung, Chetan Poudel, Tessa Sinnige, Marie C Lechler, Nicole Schlörit, Meng Lu, Romain F Laine, Claire H Michel, Michele Vendruscolo, Clemens F Kaminski, Gabriele S Kaminski Schierle, Della C David.
      Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.
    Keywords:  C. elegans; cell biology; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.43059
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