bims-apauto 2021-06-27 papers

Issue of 2021–06–27
eight papers selected by
Su Hyun Lee, Seoul National University

Annu Rev Cell Dev Biol. 2021 Jun 21.

Selective autophagy is the lysosomal degradation of specific intracellular components sequestered into autophagosomes, late endosomes, or lysosomes through the activity of selective autophagy receptors (SARs). SARs interact with autophagy-related (ATG)8 family proteins via sequence motifs called LC3-interacting region (LIR) motifs in vertebrates and Atg8-interacting motifs (AIMs) in yeast and plants. SARs can be divided into two broad groups: soluble or membrane bound. Cargo or substrate selection may be independent or dependent of ubiquitin labeling of the cargo. In this review, we discuss mechanisms of mammalian selective autophagy with a focus on the unifying principles employed in substrate recognition, interaction with the forming autophagosome via LIR-ATG8 interactions, and the recruitment of core autophagy components for efficient autophagosome formation on the substrate. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-cellbio-120219-035530

Genes Dev. 2021 Jun 24.

Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis.

Jenny A Rudnick, Teresa Monkkonen, Florie A Mar, James M Barnes, Hanna Starobinets, Juliet Goldsmith, Srirupa Roy, Sofía Bustamante Eguiguren, Valerie M Weaver, Jayanta Debnath.

Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia.

Keywords: autophagy; breast cancer; cancer-associated fibroblasts; collagen; tumor microenvironment

DOI: https://doi.org/10.1101/gad.345629.120

Cancer Control. 2021 Jan-Dec;28:28 10732748211019138

Role of Autophagy and Apoptosis in Acute Lymphoblastic Leukemia.

Fang-Liang Huang, Sheng-Jie Yu, Chia-Ling Li.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an excessive number of immature lymphocytes, including immature precursors of both B- and T cells. ALL affects children more often than adults. Immature lymphocytes lead to arrested differentiation and proliferation of cells. Its conventional treatments involve medication with dexamethasone, vincristine, and other anticancer drugs. Although the current first-line drugs can achieve effective treatment, they still cannot prevent the recurrence of some patients with ALL. Treatments have high risk of recurrence especially after the first remission. Currently, novel therapies to treat ALL are in need. Autophagy and apoptosis play important roles in regulating cancer development. Autophagy involves degradation of proteins and organelles, and apoptosis leads to cell death. These phenomena are crucial in cancer progression. Past studies reported that many potential anticancer agents regulate intracellular signaling pathways.
METHODS: The authors discuss the recent research findings on the role of autophagy and apoptosis in ALL.
RESULTS: The autophagy and apoptosis are widely used in the treatment of ALL. Most studies showed that many agents regulate autophagy and apoptosis in ALL cell models, clinical trials, and ALL animal models.
CONCLUSIONS: In summary, activating autophagy and apoptosis pathways are the main strategies for ALL treatments. For ALL, combining new drugs with traditional chemotherapy and glucocorticoids treatments can achieve the greatest therapeutic effect by activating autophagy and apoptosis.

Keywords: acute lymphoblastic leukemia; apoptosis; autophagy

DOI: https://doi.org/10.1177/10732748211019138

Autophagy. 2021 Jun 23. 1-28

Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective.

Sanjana Kumariya, Vaibhave Ubba, Rajesh K Jha, Jiaur R Gayen.

Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ affected in PCOS is the ovary and its distressed functioning elicits disturbed reproductive outcomes. In the ovary, macroautophagy/autophagy performs a pivotal role in directing the chain of events starting from oocytes origin until its fertilization. Recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. Defective autophagy in the follicular cells during different stages of follicles is observed in the PCOS ovary. Exploring different autophagy pathways provides a platform for predicting the possible cause of altered ovarian physiology in PCOS. In this review, we have emphasized autophagy's role in governing follicular development under normal circumstances and in PCOS, including significant abnormalities associated with PCOS such as anovulation, hyperandrogenemia, metabolic disturbances, and related abnormality. So far, few studies have linked autophagy and PCOS and propose its essential role in PCOS progression. However, detailed knowledge in this area is lacking. Here we have summarized the latest knowledge related to autophagy associated with PCOS. This review's main objective is to provide a background of autophagy in the ovary, its possible connection with PCOS and suggested a novel proposal for future studies to aid a better understanding of PCOS pathogenesis.Abbreviations: AE: androgen excess; AF: antral follicle; AKT/PKB: AKT serine/threonine kinase; AMH: anti-Mullerian hormone; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BMP: bone morphogenetic protein; CASP3: caspase 3; CL: corpus luteum; CYP17A1/P450C17: cytochrome P450 family 17 subfamily A member 1; CYP19A1: cytochrome P450 family 19 subfamily A member 1; DHEA: dehydroepiandrosterone; EH: endometrial hyperplasia; FF: follicular fluid; FOXO: forkhead box O; FSH: follicle stimulating hormone; GC: granulosa cell; GDF: growth differentiation factor; HA: hyperandrogenemia; HMGB1: high mobility group box 1; IGF1: insulin like growth factor 1; INS: insulin; IR: insulin resistance; LHCGR/LHR: luteinizing hormone/choriogonadotropin receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin complex; NAFLD: nonalcoholic fatty liver disease; NFKB: nuclear factor kappa B; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; oxLDL: oxidized low-density lipoproteins; PA: palmitic acid; PCOS: polycystic ovary syndrome; PF: primary follicle; PGC: primordial germ cell; PI3K: phosphoinositide 3-kinase; PMF: primordial follicle; ROS: reactive oxygen species; RP: resting pool; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; T2DM: type 2 diabetes mellitus; TC: theca cell; TUG1: taurine up-regulated 1.

Keywords: Autophagy; LC3; autophagy-related proteins; beclin 1; follicle development; follicular atresia; granulosa cells death; polycystic ovary syndrome

DOI: https://doi.org/10.1080/15548627.2021.1938914

Autophagy. 2021 Jun 21. 1-17

BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy.

Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y Wang, Motao Zhu, Rong-Fu Wang.

Macroautophagy/autophagy-related proteins regulate infectious and inflammatory diseases in autophagy-dependent or -independent manner. However, the role of a newly identified mammalian-specific autophagy protein-BECN2 (beclin 2) in innate immune regulation is largely unknown. Here we showed that loss of BECN2 enhanced the activities of NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes upon ligand stimulations. Mechanistically, BECN2 interacted with inflammasome sensors and mediated their degradation through a ULK1- and ATG9A-dependent, but BECN1-WIPI2-ATG16L1-LC3-independent, non-canonical autophagic pathway. BECN2 recruited inflammasome sensors on ATG9A+ vesicles to form a complex (BECN2-ATG9A-sensors) upon ULK1 activation. Three soluble NSF attachment protein receptor (SNARE) proteins (SEC22A, STX5, and STX6) were further shown to mediate the BECN2-ATG9A-dependent inflammasome sensor degradation. Loss of BECN2 promoted alum-induced peritonitis, which could be rescued by the ablation of CASP1 in Becn2-deficient mice. Hence, BECN2 negatively regulated inflammasome activation to control inflammation, serving as a potential therapeutic target for the treatment of infectious and inflammatory diseases.Abbreviations: AIM2: absent in melanoma 2; ATG: autophagy related; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cells; BMDM: bone marrow-derived macrophages; CASP1: caspase 1; CQ: chloroquine; gMDSC: granulocytic myeloid-derived suppressor cells; IL: interleukin; LPS: lipopolysaccharide; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; mMDSC: monocytic myeloid-derived suppressor cells; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PYCARD/ASC: apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; SNAREs: soluble NSF attachment protein receptors; STX5: syntaxin 5; STX6: syntaxin 6; ULK1: unc-51 like autophagy activating kinase 1; WIPI: WD repeat domain, phosphoinositide interacting.

Keywords: ATG9A; Alum-induced peritonitis; BECN2; STX5-STX6-SEC22A-mediated membrane fusion; inflammasome; non-canonical autophagy

DOI: https://doi.org/10.1080/15548627.2021.1934270

Autophagy. 2021 Jun 22. 1-2

AMBRA1 has an impact on melanoma development beyond autophagy.

Luca Di Leo, Daniela De Zio.

AMBRA1 (autophagy/beclin 1 regulator 1) is a multifunctional scaffold protein involved in several cellular processes spanning from cell proliferation to apoptosis and to regulation of macroautophagy/autophagy. Our recent publication revealed that Ambra1 has an antitumorigenic role in melanoma, the most aggressive and deadly skin cancer. We have indeed collected data indicating that the increased proliferative and invasive/metastatic features that we observed in ambra1-ablated melanomas are related to a remarkable regulation by Ambra1 on cellular processes which are beyond autophagy. Our study therefore sheds light on intriguing processes affected by Ambra1 which can be exploited as therapeutic targets in AMBRA1 low-expressing melanoma.

Keywords: AMBRA1; FAK1; GEMMs; cyclin D1; melanoma; metastasis; proliferation

DOI: https://doi.org/10.1080/15548627.2021.1940608

EMBO J. 2021 Jun 25. e108777

ZZ domains keep cytosol to vacuole delivery whiZZing along.

Yutaro Hama, Sidi Zhang, Noboru Mizushima.

Selective autophagy relies on adaptor proteins to bind and transport cargos (or substrates) to the lysosome or vacuole, yet the mechanisms for cargo recognition are not well understood. In this issue, Wang et al (2021) showed that in the fission yeast, Nbr1, a homolog of a mammalian selective autophagy adaptor, recognizes vacuolar hydrolases Ams1 and Ape4 through both versatile and cargo-specific interactions with the Nbr1 ZZ1 domain.

DOI: https://doi.org/10.15252/embj.2021108777

EMBO J. 2021 Jun 25. e107497

Molecular and structural mechanisms of ZZ domain-mediated cargo selection by Nbr1.

Ying-Ying Wang, Jianxiu Zhang, Xiao-Man Liu, Yulu Li, Jianhua Sui, Meng-Qiu Dong, Keqiong Ye, Li-Lin Du.

In selective autophagy, cargo selectivity is determined by autophagy receptors. However, it remains scarcely understood how autophagy receptors recognize specific protein cargos. In the fission yeast Schizosaccharomyces pombe, a selective autophagy pathway termed Nbr1-mediated vacuolar targeting (NVT) employs Nbr1, an autophagy receptor conserved across eukaryotes including humans, to target cytosolic hydrolases into the vacuole. Here, we identify two new NVT cargos, the mannosidase Ams1 and the aminopeptidase Ape4, that bind competitively to the first ZZ domain of Nbr1 (Nbr1-ZZ1). High-resolution cryo-EM analyses reveal how a single ZZ domain recognizes two distinct protein cargos. Nbr1-ZZ1 not only recognizes the N-termini of cargos via a conserved acidic pocket, similar to other characterized ZZ domains, but also engages additional parts of cargos in a cargo-specific manner. Our findings unveil a single-domain bispecific mechanism of autophagy cargo recognition, elucidate its underlying structural basis, and expand the understanding of ZZ domain-mediated protein-protein interactions.

Keywords: Schizosaccharomyces pombe ; ZZ domain; autophagy receptor; selective autophagy

DOI: https://doi.org/10.15252/embj.2020107497