A switch from canonical to noncanonical autophagy shapes B cell responses

Martínez, Núria; Maldonado, Paula; Gasparrini, Francesca; Frederico, Bruno; Aggarwal, Shweta; Gaya, Mauro; Tsui, C. Kimberly; Burbage, Marianne; Keppler, Selina J.; Montaner, Beatriz; Jefferies, Harold B.J.; Nair, Usha; Zhao, Yan; Domart, Marie-Charlotte; Collinson, Lucy M.; Bruckbauer, Andreas; Tooze, Sharon A.; Batista, Facundo D.

doi:10.1126/science.aal3908

Cited by 92 publications

(107 citation statements)

References 29 publications

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“…CQ was recently shown to induce LC3 conjugation onto endosomal membranes [49] and subsequently this event was attributed to the induction of a non-canonical form of autophagy upon short-term treatment. This non-canonical form of autophagy does not involve ATG13, ATG9A and PIK3C3/ VPS34 [29,87]. We also found that CQ indeed stimulates a mild autophagic sequestration response for a short period, which is in line with early studies that showed a peak in autophagic vesicle appearance within the first 3 h of exposure to CQ [9,64,67].…”

Section: Discussionsupporting

confidence: 91%

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion

et al. 2018

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Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradation. Autophagy is involved in the pathophysiology of numerous diseases and its modulation is beneficial for the outcome of numerous specific diseases. Several lysosomal inhibitors such as bafilomycin A (BafA), protease inhibitors and chloroquine (CQ), have been used interchangeably to block autophagy in in vitro experiments assuming that they all primarily block lysosomal degradation. Among them, only CQ and its derivate hydroxychloroquine (HCQ) are FDA-approved drugs and are thus currently the principal compounds used in clinical trials aimed to treat tumors through autophagy inhibition. However, the precise mechanism of how CQ blocks autophagy remains to be firmly demonstrated. In this study, we focus on how CQ inhibits autophagy and directly compare its effects to those of BafA. We show that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle. Furthermore, CQ induces an autophagy-independent severe disorganization of the Golgi and endo-lysosomal systems, which might contribute to the fusion impairment. Strikingly, HCQ-treated mice also show a Golgi disorganization in kidney and intestinal tissues. Altogether, our data reveal that CQ and HCQ are not bona fide surrogates for other types of late stage lysosomal inhibitors for in vivo experiments. Moreover, the multiple cellular alterations caused by CQ and HCQ call for caution when interpreting results obtained by blocking autophagy with this drug.

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Section: Discussionsupporting

confidence: 91%

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion

et al. 2018

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“…G9A inhibitors have been reported to induce autophagy, this was also observed in the B-cell response to this G9A inhibitor with rapid induction of features consistent with autophagy in ABCs following UNC0638 treatment (Supplemental Figure 11B and C). Autophagy can have a protective role in PC differentiation, 51, 52 and despite the stress response phenotypic differentiation showed limited differences with modest impairment in the downregulation of CD20 and the upregulation of CD38 (Supplemental Figure 11D). Furthermore, consistent with a delayed impact as would be anticipated with an epigenetic mechanism cell division was modestly impaired at day 4 (24h of treatment) and delayed by one generation at day 5 and 6 where the population mode for UNC0638 treated cells fell at generation 6 rather than 7 (Supplemental Figure 11E).…”

Section: Resultsmentioning

confidence: 99%

A dichotomy in association of core transcription factors and gene regulation during the activated B-cell to plasmablast transition

Cocco

Care

Al-Maskari

et al. 2019

Preprint

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The activated B-cell (ABC) to plasmablast transition is the cusp of antibody secreting cell (ASC) differentiation but is incompletely defined. We apply expression time-courses, parsimonious gene correlation network analysis, and ChIP-seq to explore this in human cells. The transition initiates with input signal loss leading within hours from cell growth dominant programs to enhanced proliferation, accompanied from 24h by ER-stress response, secretory optimization and upregulation of ASC features. Clustering of genomic occupancy for ASC transcription factors (TFs) IRF4, BLIMP1 and XBP1 with CTCF and histone marks defines distinct patterns for each factor in plasmablasts. Integrating TF-associated clusters and modular gene expression identifies a dichotomy: XBP1 and IRF4 significantly link to gene modules induced in plasmablasts, but not to modules of repressed genes, while BLIMP1 links to modules of ABC genes repressed in plasmablasts but is not significantly associated with modules induced in plasmablasts. Pharmacological inhibition of the G9A (EHMT2) histone-methytransferase, a BLIMP1 co-factor that catalyzes repressive H3K9me2 marks, leaves functional ASC differentiation intact but de-represses ABC-state genes. Thus, in human plasmablasts IRF4 and XBP1 emerge as the dominant association with ASC gene expression, while BLIMP1 links to repressed modules with particular focus in repression of the B-cell activation state.

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“…V-ATPase inhibitor bafilomycin A (BafA) blocks LC3II lysosomal degradation during canonical autophagy. Chloroquine (CQ) inhibits the fusion between the autophagosome and lysosome, thereby rendering it capable of revealing total autophagic flux, inclusive of both canonical and noncanonical autophagy (33,34). Thus, the difference between the effects of CQ versus BafA on LC3-II/I ratios is attributed to noncanonical autophagy.…”

Section: Wipi1 Regulates Map4 Expression Under Conditions Of Aldostermentioning

confidence: 99%

WIPI1 is a conserved mediator of right ventricular failure

Tzimas¹,

Rau²,

Buergisser³

et al. 2019

JCI Insight

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A switch from canonical to noncanonical autophagy shapes B cell responses

Cited by 92 publications

References 29 publications

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion

A dichotomy in association of core transcription factors and gene regulation during the activated B-cell to plasmablast transition

WIPI1 is a conserved mediator of right ventricular failure

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