Follicular lymphoma–associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR

Wang, Fangyang; Gatica, Damián; Zhang, Ying; Peterson, Luke F.; Kim, Peter K.; Bernard, Denzil; Saiya-Cork, Kamlai; Wang, Shaomeng; Kaminski, Mark; Chang, Alfred E.; Phillips, Tycel; Klionsky, Daniel J.; Malek, Sami N.

doi:10.1172/jci98288

Cited by 24 publications

(14 citation statements)

References 89 publications

(97 reference statements)

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“…In addition, it was found that V-ATPase is critical for sensing of amino acids and subsequent activation of mTOR complex 1 (mTORC1). Amino acids stimulate recruitment of mTORC1 to the lysosomal surface, where its direct activator,Ragulator(a family of four GTPases that are related to Ras, RagGTPases) was associatedtightly with the V-ATPase [69,70]. were markedly promotedby V-ATPase de ciency, which was consistent withtheactivation of JNK signaling in glial cells, monocyte-derived macrophages and RAW 264 [71][72][73].…”

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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V-ATPase Deficiency Aggravates Hypoxia-induced Spermatogenesis Reduction by Promoting Spermatocyte Apoptosis via the JNK/c-Jun Pathway in Mice

Yin

Han

et al. 2021

Preprint

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Spermatocyte apoptosis is the primary cause of poor outcome after hypoxia-triggered spermatogenesis reduction (HSR). The vacuolar H+-ATPase (V-ATPase) has been found to be involved in the regulation of hypoxia-induced GC-2 cells apoptosis. However, the mechanism of V-ATPase regulating spermatocyte apoptosis after HSR hasnot been well elucidated. In this study, HSRmodel was established by hypoxia exposure in vivo in V-ATPase-knockout (V-ATPase-/-) and wild-type (WT) mice to investigate theeffectof V-ATPase deficiency on spermatocyte apoptosis. GC-2, amouse pachytene spermatocyte-derived cell line, was introduced in vitro experiments. The sperm count and spermatogenic apoptosis were recorded after 60 d of hypoxia exposure in HSR model. The apoptosis of GC-2 cells was detected by flow cytometry and TUNEL staining. The expression of JNK/c-Jun was evaluated by RNA-seq or western blot. The expression of DR5 and caspase-8 was evaluated by RT-qPCR and western blot. The expression of V-ATPase was determined by western blot in the presence and absence ofLenti-transcription factor EB (TFEB).C-Jun interference was used for evaluating the role of JNK in regulating the apoptosis of GC-2 cells byTUNEL and flow cytometry. The in vivo results suggested that hypoxia induced spermatogenesis reduction and downregulation of V-ATPase. Moreover, V-ATPase deficiency resulted in moresevere spermatogenesis reduction after hypoxia exposure. The spermatogenesis reduction was associated with exacerbation of spermatocyte apoptosis. Hypoxia down-regulated the transcription of V-ATPase through inhibiting TFEB and its nuclear translocation. The mRNA and protein expressions of V-ATPaseincreased after TFEB overexpression in GC-2 cells. Moreover, V-ATPase deficiency enhanced JNK/c-Jun activation and related DR-apoptotic pathwayin GC-2 cells.However,inhibition of c-Jun attenuated V-ATPase deficiency-induced GC-2 cells apoptosis in vitro and HSR in vivo. In conclusion, JNK/c-Jun was involved in the enhancement of V-ATPase-mediated HSR in V-ATPase -/- mice. V-ATPase deficiency aggravates spermatocyte apoptosis, which may account forthe poor spermatogenesis outcomes of V-ATPase-/- mice. The discoveredfunction of V-ATPase modulating spermatocyte apoptosis indicates its potential therapeutic effect against HSR.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

V-ATPase Deficiency Aggravates Hypoxia-induced Spermatogenesis Reduction by Promoting Spermatocyte Apoptosis via the JNK/c-Jun Pathway in Mice

Yin

Han

et al. 2021

Preprint

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“…Similar disease-specific patterns were also observed for signaling genes; for example, TCF3 and ID3 have important functions in normal germinal center B-cells(44), but mutations of these genes are specifically enriched within BL and are rarely found in the other GCB-derived malignancies, DLBCL and FL. Similarly, the ATP6AP1 and ATP6V1B2 genes that function in mTOR signaling(45, 46) are specifically mutated in FL, and the DUSP2 gene which inactivates ERK1/2(47) and STAT3(48) is specifically mutated in DLBCL. The disease-specific patterns of genetic alterations therefore reveal subtle but important differences in how each subtype of B-NHL perturbs hallmark features.…”

Section: Resultsmentioning

confidence: 99%

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma

John

Tadros

Bouska

et al. 2019

Preprint

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B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level, but other less common subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 755 B-NHL tumors at high depth; primarily including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated across major subtypes, such as the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations that are pathognomonic. The cumulative burden of mutations within a single cluster were more significantly discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic epistasis that contribute to disease etiology. We therefore provide a framework of co-occurring mutations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis of B-NHL subtypes.KEY POINTSGenetic perturbation of the ubiquitin proteasome system is an emerging hallmark of B-cell non-Hodgkin lymphoma (B-NHL).Co-occurring sets of genetic alterations define B-NHL subtypes and likely represent epistatic interactions.

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“…The following references appear in the supplemental information: Anderson et al., 2018 ; Austin et al., 2012 ; Bhattacharyya et al., 2011 ; Carcel-Trullols et al., 2017 ; Chang et al., 2014 ; Chen et al., 2013 ; Chung et al., 2019 ; De Seranno et al., 2006 ; Dera et al., 2019 ; Erasmus et al., 2016 ; Gittleman et al., 2016 ; Gu et al., 2017 ; Hallett et al., 2018 ; Hamdan et al, 2014 ; Hedberg-Oldfors et al., 2019 ; Helbig et al., 2019 ; Hoock et al., 1997 ; Hung et al., 2014 ; Kang et al., 2017 ; Khalid et al., 2016 ; Kook et al., 2016 ; Kostelansky et al., 2006 ; Levi and Finazzi, 2014 ; Li et al., 2020 ; Macri et al., 2015 ; Martinez and Goud, 1998 ; Mizunoe et al., 2020 ; Mohammadzadeh et al., 2020 ; Mohler et al., 2003 ; Määttä et al., 1994 ; Nguyen et al., 2019 ; Orenstein and Cuervo, 2010 ; Rezaie et al., 2002 ; Salabarria et al., 2020 ; Scheidel et al, 2018 ; Sjodin et al., 2019 ; Tan et al., 2015 ; Tang et al., 2019 ; Vaibhava et al., 2012 ; Wang et al., 2019a , 2019b ; Ye et al, 2020 ; Zielonka et al., 2019 .…”

Section: Supporting Citationsunclassified

A modified density gradient proteomic-based method to analyze endolysosomal proteins in cardiac tissue

et al. 2021

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Summary The importance of lysosomes in cardiac physiology and pathology is well established, and evidence for roles in calcium signaling is emerging. We describe a label-free proteomics method suitable for small cardiac tissue biopsies based on density-separated fractionation, which allows study of endolysosomal (EL) proteins. Density gradient fractions corresponding to tissue lysate; sarcoplasmic reticulum (SR), mitochondria (Mito) (1.3 g/mL); and EL with negligible contamination from SR or Mito (1.04 g/mL) were analyzed using Western blot, enzyme activity assay, and liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis (adapted discontinuous Percoll and sucrose differential density gradient). Kyoto Encyclopedia of Genes and Genomes, Reactome, Panther, and Gene Ontology pathway analysis showed good coverage of RAB proteins and lysosomal cathepsins (including cardiac-specific cathepsin D) in the purified EL fraction. Significant EL proteins recovered included catalytic activity proteins. We thus present a comprehensive protocol and data set of guinea pig atrial EL organelle proteomics using techniques also applicable for non-cardiac tissue.

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Follicular lymphoma–associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR

Cited by 24 publications

References 89 publications

V-ATPase Deficiency Aggravates Hypoxia-induced Spermatogenesis Reduction by Promoting Spermatocyte Apoptosis via the JNK/c-Jun Pathway in Mice

V-ATPase Deficiency Aggravates Hypoxia-induced Spermatogenesis Reduction by Promoting Spermatocyte Apoptosis via the JNK/c-Jun Pathway in Mice

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma

A modified density gradient proteomic-based method to analyze endolysosomal proteins in cardiac tissue

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