Autophagy最新文献

{"title":"Why nuclease free water ruined my experiment (but at least it was free), or why the short dash matters.","authors":"Daniel J Klionsky","doi":"10.1080/15548627.2024.2394711","DOIUrl":"10.1080/15548627.2024.2394711","url":null,"abstract":"<p><p>There are different types of punctuation marks that are referred to as dashes. These include the short dash or hyphen (-), the en dash (-) and the em dash (-). Each of these marks has a purpose, some of which I have discussed previously. In this editor's corner I am going to try to convince you of the importance of the short dash/hyphen. This is important stuff, so please bear with me. As an editor, and in the interests of scientific accuracy, I am trying to/having to correct errors involving the short dash all of the time. But I will not always be here, and I do not have a chance to edit your papers submitted to other journals (although why you would submit to another journal is an entire topic in and of itself), so it behooves you to pay attention.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The different roles of V-ATPase a subunits in phagocytosis/endocytosis and autophagy.","authors":"Qi Chen, Hanjing Kou, Doris Lou Demy, Wei Liu, Jianchao Li, Zilong Wen, Philippe Herbomel, Zhibin Huang, Wenqing Zhang, Jin Xu","doi":"10.1080/15548627.2024.2366748","DOIUrl":"10.1080/15548627.2024.2366748","url":null,"abstract":"<p><p>Microglia are specialized macrophages responsible for the clearance of dead neurons and pathogens by phagocytosis and degradation. The degradation requires phagosome maturation and acidification provided by the vesicular- or vacuolar-type H⁺-translocating adenosine triphosphatase (V-ATPase), which is composed of the cytoplasmic V₁ domain and the membrane-embedded V_o domain. The V-ATPase a subunit, an integral part of the V_o domain, has four isoforms in mammals. The functions of different isoforms on phagosome maturation in different cells/species remain controversial. Here we show that mutations of both the V-ATPase Atp6v0a1 and Tcirg1b/Atp6v0a3 subunits lead to the accumulation of phagosomes in zebrafish microglia. However, their mechanisms are different. The V-ATPase Atp6v0a1 subunit is mainly distributed in early and late phagosomes. Defects of this subunit lead to a defective transition from early phagosomes to late phagosomes. In contrast, The V-ATPase Tcirg1b/Atp6v0a3 subunit is primarily located on lysosomes and regulates late phagosome-lysosomal fusion. Defective Tcirg1b/Atp6v0a3, but not Atp6v0a1 subunit leads to reduced acidification and impaired macroautophagy/autophagy in microglia. We further showed that ATP6V0A1/a1 and TCIRG1/a3 subunits in mouse macrophages preferentially located in endosomes and lysosomes, respectively. Blocking these subunits disrupted early-to-late endosome transition and endosome-to-lysosome fusion, respectively. Taken together, our results highlight the essential and conserved roles played by different V-ATPase subunits in multiple steps of phagocytosis and endocytosis across various species.<b>Abbrevations</b>: Apoe: apolipoprotein E; ANXA5/annexin V: annexin A5; ATP6V0A1/a1: ATPase H+-transporting V0 subunit a1; ATP6V0A2/a2: ATPase H+-transporting V0 subunit a2; ATP6V0A4/a4: ATPase H+-transporting V0 subunit a4; dpf: days post-fertilization; EEA1: early endosome antigen 1; HOPS: homotypic fusion and protein sorting; LAMP1: lysosomal associated membrane protein 1; Lcp1: lymphocyte cytosolic protein 1 (L-plastin); Map1lc3/Lc3: microtubule-associated protein 1 light chain 3; NR: neutral red; PBS: phosphate-buffered saline; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol (3,5)-bisphosphate; RAB4: RAB4, member RAS oncogene family; RAB5: RAB5, member RAS oncogene family; RAB7: RAB7, member RAS oncogene family; TCIRG1/Atp6v0a3/a3: T cell immune regulator 1, ATPase H+-transporting V0 subunit a3; V-ATPase: vacuolar-type H+-translocating adenosine triphosphatase; Xla.Tubb2b/NBT: tubulin beta 2B class IIb.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141319261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel <i>lnc-HZ12</i> suppresses autophagy degradation of BBC3 by preventing its interactions with HSPA8 to induce trophoblast cell apoptosis.","authors":"Jingsong Zhao, Zhongyan Xu, Jiayu Xie, Tingting Liang, Rong Wang, Weina Chen, Chenyang Mi, Peng Tian, Jiarong Guo, Huidong Zhang","doi":"10.1080/15548627.2024.2362122","DOIUrl":"10.1080/15548627.2024.2362122","url":null,"abstract":"<p><p>Abnormal expression of long non-coding RNAs (lncRNAs) is associated with the dysfunctions of human trophoblast cells and the occurrence of miscarriage (abnormal early embryo loss). BBC3/PUMA (BCL2 binding component 3) plays significant roles in regulation of cell apoptosis. However, whether specific lncRNAs might regulate BBC3 in trophoblast cells and further induce apoptosis and miscarriage remains completely unclear. Through screening, we identified a novel <i>lnc-HZ12</i>, which was significantly highly expressed in villous tissues of recurrent miscarriage (RM) patients relative to their healthy control (HC) group. <i>Lnc-HZ12</i> suppressed chaperone-mediated autophagy (CMA) degradation of BBC3, promoted trophoblast cell apoptosis, and was associated with miscarriage. In mechanism, <i>lnc-HZ12</i> downregulated the expression levels of chaperone molecules HSPA8 and LAMP2A in trophoblast cells. Meanwhile, <i>lnc-HZ12</i> (mainly <i>lnc-HZ12-</i>SO2 region in F2 fragment) and HSPA8 competitively bound with the ₁₆₉RVLYNL₁₇₄ patch on BBC3, which prevented BBC3 from interactions with HSPA8 and impaired the formation of BBC3-HSPA8-LAMP2A complex for CMA degradation of BBC3. Thus, <i>lnc-HZ12</i> upregulated the BBC3-CASP9-CASP3 pathway and induced trophoblast cell apoptosis. In villous tissues, <i>lnc-HZ12</i> was highly expressed, CMA degradation of BBC3 was suppressed, and the apoptosis levels were higher in RM vs HC villous tissues, all of which were associated with miscarriage. Interestingly, knockdown of murine <i>Bbc3</i> could efficiently suppress placental apoptosis and alleviate miscarriage in a mouse miscarriage model. Taken together, our results indicated that <i>lnc-HZ12</i> and BBC3 played important roles in trophoblast cell apoptosis and miscarriage and might act as attractive targets for miscarriage treatment.<b>Abbreviation</b>: 7-AAD: 7-aminoactinomycin D; BaP: benzopyrene; BBC3/PUMA: BCL2 binding component 3; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DMSO: dimethyl sulfoxide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HC: healthy control; HSPA8: heat shock protein family A (Hsp70) member 8; IP: immunoprecipitation; LAMP2A: lysosomal associated membrane protein 2; LncRNA: long non-coding RNA; mRNA: messenger RNA; MT: mutant-type; NC: negative control; NSO: nonspecific oligonucleotide; PARP1: poly(ADP-ribose) polymerase 1; RIP: RNA immunoprecipitation; RM: recurrent miscarriage; TBP: TATA-box binding protein; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An interplay between biomolecular condensates and SNARE proteins regulates plant autophagy.","authors":"Ruixi Li, Lei Pang","doi":"10.1080/15548627.2024.2408188","DOIUrl":"https://doi.org/10.1080/15548627.2024.2408188","url":null,"abstract":"<p><p>A recent study in our group reports a new \"condensates to VPS41-associated phagic vacuole (VAPVs) conversion pathway\" that is essential for macroautophagy/autophagy degradation in plant cells. Here, we compare the autophagy process between plants and other eukaryotic systems and discuss the potential roles of biomolecular condensates and synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins in plant autophagy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atg44/Mdi1/mitofissin facilitates Dnm1-mediated mitochondrial fission.","authors":"Kentaro Furukawa, Manabu Hayatsu, Kentaro Okuyama, Tomoyuki Fukuda, Shun-Ichi Yamashita, Keiichi Inoue, Shinsuke Shibata, Tomotake Kanki","doi":"10.1080/15548627.2024.2360345","DOIUrl":"10.1080/15548627.2024.2360345","url":null,"abstract":"<p><p>Mitochondria undergo fission and fusion, and their coordinated balance is crucial for maintaining mitochondrial homeostasis. In yeast, the dynamin-related protein Dnm1 is a mitochondrial fission factor acting from outside the mitochondria. We recently reported the mitochondrial intermembrane space protein Atg44/mitofissin/Mdi1/Mco8 as a novel fission factor, but the relationship between Atg44 and Dnm1 remains elusive. Here, we show that Atg44 is required to complete Dnm1-mediated mitochondrial fission under homeostatic conditions. Atg44-deficient cells often exhibit enlarged mitochondria with accumulated Dnm1 and rosary-like mitochondria with Dnm1 foci at constriction sites. These mitochondrial constriction sites retain the continuity of both the outer and inner membranes within an extremely confined space, indicating that Dnm1 is unable to complete mitochondrial fission without Atg44. Moreover, accumulated Atg44 proteins are observed at mitochondrial constriction sites. These findings suggest that Atg44 and Dnm1 cooperatively execute mitochondrial fission from inside and outside the mitochondria, respectively.<b>Abbreviation:</b> ATG: autophagy related; CLEM: correlative light and electron microscopy; EM: electron microscopy; ER: endoplasmic reticulum; ERMES: endoplasmic reticulum-mitochondria encounter structure; GA: glutaraldehyde; GFP: green fluorescent protein; GTP: guanosine triphosphate: IMM: inner mitochondrial membrane; IMS: intermembrane space; OMM: outer mitochondrial membrane; PB: phosphate buffer; PBS: phosphate-buffered saline; PFA: paraformaldehyde; RFP: red fluorescent protein; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secretory autophagy - a new paradigm regulating synaptic plasticity.","authors":"Yen-Ching Chang, Karen T Chang","doi":"10.1080/15548627.2024.2370179","DOIUrl":"10.1080/15548627.2024.2370179","url":null,"abstract":"<p><p>When exposed to new experiences or changes in the environment, neurons rapidly remodel their synaptic structure and function in a process called activity-induced synaptic remodeling. This process is necessary for transforming transient experiences into stable, lasting memories. The molecular mechanisms underlying acute, activity-dependent synaptic changes are not well understood, partly because processes regulating synaptic plasticity and neurodevelopment are intricately linked. By using an RNAi screen in <i>Drosophila</i> targeting genes associated with human nervous system function, we found that while macroautophagy (referred to as autophagy) is fundamental for both synapse development and synaptic plasticity, activity-induced synaptic remodeling does not rely on genes associated with lysosomal degradation. These findings suggest a requirement for the unconventional secretory autophagy pathway in regulating synaptic plasticity, wherein autophagosomes, instead of fusing with lysosomes for degradation, fuse with the plasma membrane to release their contents extracellularly. To test this hypothesis, we knocked down Sec22, Snap29, and Rab8, molecular components required for secretory autophagy, all of which disrupted structural and functional plasticity. Additionally, by monitoring autophagy, we demonstrated that neuronal activity suppresses degradative autophagy to shift the pathway toward secretory autophagy release. Our work unveils secretory autophagy as a novel trans-synaptic signaling mechanism crucial for activity-induced synaptic remodeling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.","authors":"Hortense de Calbiac, Solène Renault, Grégoire Haouy, Vincent Jung, Kevin Roger, Qihui Zhou, Maria-Letizia Campanari, Loïc Chentout, Doris Lou Demy, Anca Marian, Nicolas Goudin, Dieter Edbauer, Chiara Guerrera, Sorana Ciura, Edor Kabashi","doi":"10.1080/15548627.2024.2358736","DOIUrl":"https://doi.org/10.1080/15548627.2024.2358736","url":null,"abstract":"<p><p>The GGGGCC hexanucleotide repeat expansion (HRE) of the <i>C9orf72</i> gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. <i>C9orf72</i> HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate <i>C9orf72</i>-related ALS disease <i>in vivo</i>, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a <i>c9orf72</i> knockdown context. We report that <i>C9orf72</i> gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon <i>c9orf72</i> downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published <i>C9orf72</i> iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RCHY1 and OPTN: an E3-ligase and an autophagy receptor required for melanophagy, respectively.","authors":"Ki Won Lee, Yong-Yeon Cho, Kwang Dong Kim","doi":"10.1080/15548627.2024.2370058","DOIUrl":"10.1080/15548627.2024.2370058","url":null,"abstract":"<p><p>Dysregulation of melanin homeostasis is implicated in causing skin pigmentation disorders, such as melasma due to hyperpigmentation and vitiligo due to hypopigmentation. Although the synthesis of melanin has been well studied, the removal of the formed skin pigment requires more research. We determined that β-mangostin, a plant-derived metabolite, induces the degradation of already-formed melanin in the mouse B16F10 cell line. The whitening effect of β-mangostin is mediated by macroautophagy/autophagy, as it was abolished by the knockdown of ATG5 or RB1CC1/FIP200, and by treatment with 3-methyladenine, a phosphatidylinositol 3-kinase complex inhibitor. However, the exact autophagy mechanism of melanosome degradation remains unknown. Selective autophagy for a specific cellular organelle requires specific E3-ligases and autophagic receptors for the target organelle. In this study, an E3-ligase, RCHY1, and an autophagy receptor, OPTN (optineurin), were identified as being essential for melanophagy in the β-mangostin-treated B16F10 cell line. As per our knowledge, this is the first report of a specific mechanism for the degradation of melanosomes, the target organelle of melanophagy. These findings are expected to broaden the scope of melanin homeostasis research and can be exploited for the development of therapeutics for skin pigmentation disorders.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When an underdog becomes a major player: the role of protein structural disorder in the Atg8 conjugation system.","authors":"Hana Popelka, Daniel J Klionsky","doi":"10.1080/15548627.2024.2357496","DOIUrl":"10.1080/15548627.2024.2357496","url":null,"abstract":"<p><p>The noncanonical ubiquitin-like conjugation cascade involving the E1 (Atg7), E2 (Atg3, Atg10), and E3 (Atg12-Atg5-Atg16 complex) enzymes is essential for incorporation of Atg8 into the growing phagophore via covalent linkage to PE. This process is an indispensable step in autophagy. Atg8 and E1-E3 enzymes are the first subset from the core autophagy protein machinery structures that were investigated in earlier studies by crystallographic analyses of globular domains. However, research over the past decade shows that many important functions in the conjugation machinery are mediated by intrinsically disordered protein regions (IDPRs) - parts of the protein that do not adopt a stable secondary or tertiary structure, which are inherently dynamic and well suited for protein-membrane interactions but are invisible in protein crystals. Here, we summarize earlier and recent findings on the autophagy conjugation machinery by focusing on the IDPRs. This summary reveals that IDPRs, originally considered dispensable, are in fact major players and a driving force in the function of the autophagy conjugation system. <b>Abbreviation</b>: AD, activation domain of Atg7; AH, amphipathic helix; AIM, Atg8-family interacting motif; CL, catalytic loop (of Atg7); CTD, C-terminal domain; FR, flexible region (of Atg3 or Atg10); GUV, giant unilammelar vesicles; HR, handle region (of Atg3); IDPR, intrinsically disordered protein region; IDPs: intrinsically disordered proteins; LIR, LC3-interacting region; NHD: N-terminal helical domain; NMR, nuclear magnetic resonance; PE, phosphatidylethanolamine; UBL, ubiquitin like.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATG16L1 in myeloid cells limits colorectal tumor growth in <i>Apc^Min/+</i> mice infected with colibactin-producing <i>Escherichia coli</i> via decreasing inflammasome activation.","authors":"Laurène Salesse, Angéline Duval, Pierre Sauvanet, Alison Da Silva, Nicolas Barnich, Catherine Godfraind, Guillaume Dalmasso, Hang Thi Thu Nguyen","doi":"10.1080/15548627.2024.2359770","DOIUrl":"10.1080/15548627.2024.2359770","url":null,"abstract":"<p><p><i>Escherichia coli</i> strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing <i>E. coli</i>), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the <i>Apc</i>^<i>Min/+</i> mice, with <i>Atg16l1</i> deficiency specifically in myeloid cells (<i>Apc</i>^<i>Min/+</i>/<i>Atg16l1[∆MC]</i>) and the corresponding control mice (<i>Apc</i>^<i>Min/+</i>), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5<i>∆clbQ</i> that does not produce colibactin. We showed that myeloid cell-specific <i>Atg16l1</i> deficiency led to an increase in the volume of colonic tumors in <i>Apc</i>^<i>Min/+</i> mice under infection with 11G5, but not with 11G5<i>∆clbQ</i>. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1β secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8⁺ T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5∆<i>clbQ</i>-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected <i>Apc</i>^<i>Min/+</i> mice <i>via</i> inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. <b>Abbreviation</b>: AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; <i>Atg16l1[∆MC]</i> mice, mice deficient for <i>Atg16l1</i> specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing <i>Escherichia coli</i>; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; <i>pks</i>, polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-α, tumor necrosis factor.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}