Molecular Biology of the Cell最新文献_第8页

Movement of the endoplasmic reticulum is driven by multiple classes of vesicles marked by Rab-GTPases. 内质网的运动是由多类以Rab-GTPases为标志的囊泡驱动的。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-12-04 DOI: 10.1091/mbc.E24-04-0197

Allison Langley, Sarah Abeling-Wang, Erinn Wagner, John Salogiannis

{"title":"Movement of the endoplasmic reticulum is driven by multiple classes of vesicles marked by Rab-GTPases.","authors":"Allison Langley, Sarah Abeling-Wang, Erinn Wagner, John Salogiannis","doi":"10.1091/mbc.E24-04-0197","DOIUrl":"10.1091/mbc.E24-04-0197","url":null,"abstract":"Peripheral endoplasmic reticulum (ER) tubules move along microtubules to interact with various organelles through membrane contact sites. Traditionally, ER moves by either sliding along stable microtubules via molecular motors or attaching to the plus ends of dynamic microtubules through tip attachment complexes (TAC). A recently discovered third process, hitchhiking, involves motile vesicles pulling ER tubules along microtubules. Previous research showed that ER hitchhikes on Rab5- and Rab7-marked endosomes, but it is uncertain whether other Rab-vesicles can do the same. In U2OS cells, we screened Rabs for their ability to cotransport with ER tubules and found that ER hitchhikes on post-Golgi vesicles marked by Rab6 (isoforms a and b). Rab6-ER hitchhiking occurs independently of ER-endolysosome contacts and TAC-mediated ER movement. Depleting Rab6 and the motility of Rab6-vesicles reduces overall ER movement. Conversely, relocating these vesicles to the cell periphery causes peripheral ER accumulation, indicating that Rab6-vesicle motility is crucial for a subset of ER movements. Proximal post-Golgi vesicles marked by TGN46 are involved in Rab6-ER hitchhiking, while late Golgi vesicles (Rabs 8/10/11/13/14) are not essential for ER movement. Our further analysis finds that ER to Golgi vesicles marked by Rab1 are also capable of driving a subset of ER movements. Taken together, our findings suggest that ER hitchhiking on Rab-vesicles is a significant mode of ER movement.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar9"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A defined tubby domain β-barrel surface region of TULP3 mediates ciliary trafficking of diverse cargoes. TULP3的一个确定的管状结构域β-管表面区域介导了多种货物的纤毛运输。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1091/mbc.E24-09-0426

Vivek Reddy Palicharla, Hemant B Badgandi, Sun-Hee Hwang, Emilie Legué, Karel F Liem, Saikat Mukhopadhyay

{"title":"A defined tubby domain β-barrel surface region of TULP3 mediates ciliary trafficking of diverse cargoes.","authors":"Vivek Reddy Palicharla, Hemant B Badgandi, Sun-Hee Hwang, Emilie Legué, Karel F Liem, Saikat Mukhopadhyay","doi":"10.1091/mbc.E24-09-0426","DOIUrl":"10.1091/mbc.E24-09-0426","url":null,"abstract":"The primary cilium is a paradigmatic subcellular compartment at the nexus of numerous cellular and morphogenetic pathways. The tubby family protein TULP3 acts as an adapter of the intraflagellar transport complex A in transporting integral membrane and membrane-associated lipidated proteins into cilia. However, the mechanisms by which TULP3 coordinates ciliary transport of diverse cargoes is not well understood. Here, we provide molecular insights into TULP3-mediated ciliary cargo recognition. We screened for critical TULP3 residues by proximity biotinylation-mass spectrometry, structural analysis, and testing TULP3 variants in human patients with hepatorenal fibrocystic disease and spina bifida. The TULP3 residues we identified 1) were located on one side of the β-barrel of the tubby domain away from the phosphoinositide binding site, 2) mediated ciliary trafficking of lipidated and transmembrane cargoes, and 3) determined proximity with these cargoes in vivo without affecting ciliary localization, phosphoinositide binding or hydrodynamic properties of TULP3. Overall, these findings implicate a specific region of one of the surfaces of the TULP3 β-barrel in ciliary trafficking of diverse cargoes. This region overlooks the β-strands 8-12 of the β-barrel and is away from the membrane anchoring phosphoinositide binding site. Targeting the TULP3-cargo interactions could provide therapeutics in ciliary trafficking diseases.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar1"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dominant negative mutations in yeast Hsp90 indicate triage decision mechanism targeting client proteins for degradation. 酵母 Hsp90 的显性负突变表明了针对客户蛋白降解的分流决策机制。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1091/mbc.E24-07-0309

Julia M Flynn, Margot E Joyce, Daniel N A Bolon

{"title":"Dominant negative mutations in yeast Hsp90 indicate triage decision mechanism targeting client proteins for degradation.","authors":"Julia M Flynn, Margot E Joyce, Daniel N A Bolon","doi":"10.1091/mbc.E24-07-0309","DOIUrl":"10.1091/mbc.E24-07-0309","url":null,"abstract":"Dominant negative (DN) mutations provide valuable tools for investigating protein mechanisms but can be difficult to isolate because of their toxic effects. We used a mutational scanning approach to identify DN mutations in yeast Hsp90. In a previous mutational scan of the ATPase domain of Hsp90, we noticed that many mutations were at very low frequency after outgrowth in cells coexpressing wildtype Hsp90. Most of these depleted variants were located at the hinge of a lid that closes over ATP. To quantify toxic effects in the hinge regions, we performed mutational scanning using an inducible promoter and identified 113 variants with strong toxic effects. We analyzed individual DN mutations in detail and found that addition of the E33A mutation that prevents ATP hydrolysis by Hsp90 abrogated the DN phenotype. FRET assays performed on individual DN mutants indicate the linkage between ATPase activity and formation of the closed structure is disrupted. DN Hsp90 decreased the expression level of two model Hsp90 clients, glucocorticoid receptor (GR) and v-src kinase. Using MG132, we found that GR was rapidly destabilized in a proteasome-dependent manner. Biochemical analyses indicate that ATP hydrolysis by Hsp90 from open conformations can lead to ubiquitin-dependent client degradation.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar5"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The CDK8 kinase module: A novel player in the transcription of translation initiation and ribosomal genes. CDK8 激酶模块：翻译起始基因和核糖体基因转录过程中的新型参与者

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1091/mbc.E24-04-0164

Brittany Friedson, Stephen D Willis, Natalia Shcherbik, Alicia N Campbell, Katrina F Cooper

{"title":"The CDK8 kinase module: A novel player in the transcription of translation initiation and ribosomal genes.","authors":"Brittany Friedson, Stephen D Willis, Natalia Shcherbik, Alicia N Campbell, Katrina F Cooper","doi":"10.1091/mbc.E24-04-0164","DOIUrl":"10.1091/mbc.E24-04-0164","url":null,"abstract":"Survival following stress is dependent upon reprogramming transcription and translation. Communication between these programs following stress is critical for adaptation but is not clearly understood. The Cdk8 kinase module (CKM) of the Mediator complex modulates the transcriptional response to various stresses. Its involvement in regulating translational machinery has yet to be elucidated, highlighting an existing gap in knowledge. Here, we report that the CKM positively regulates a subset of ribosomal protein (RP) and translation initiation factor (TIF)-encoding genes under physiological conditions in Saccharomyces cerevisiae. In mouse embryonic fibroblasts and HCT116 cells, the CKM regulates unique sets of RP and TIF genes, demonstrating some conservation of function across species. In yeast, this is mediated by Cdk8 phosphorylation of one or more transcription factors which control RP and TIF expression. Conversely, the CKM is disassembled following nutrition stress, permitting repression of RP and TIF genes. The CKM also plays a transcriptional role important for promoting cell survival, particularly during translational machinery stress triggered by ribosome-targeting antibiotics. Furthermore, in mammalian cells, the activity of CDK8 and its paralogue, CDK19, promotes cell survival following ribosome inhibition. These results provide mechanistic insights into the CKM's role in regulating expression of a subset of genes associated with translation.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar2"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GpsB interacts with FtsZ in multiple species and may serve as an accessory Z-ring anchor. 在多个物种中，GpsB 与 FtsZ 相互作用，可能充当 Z 环的辅助锚。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1091/mbc.E24-07-0302

Dipanwita Bhattacharya, Asher King, Lily McKnight, Pilar Horigian, Prahathees J Eswara

{"title":"GpsB interacts with FtsZ in multiple species and may serve as an accessory Z-ring anchor.","authors":"Dipanwita Bhattacharya, Asher King, Lily McKnight, Pilar Horigian, Prahathees J Eswara","doi":"10.1091/mbc.E24-07-0302","DOIUrl":"10.1091/mbc.E24-07-0302","url":null,"abstract":"Bacterial cytokinesis commences when a tubulin-like GTPase, FtsZ, forms a Z-ring to mark the division site. Synchronized movement of Z-ring filaments and peptidoglycan synthesis along the axis of division generates a division septum to separate the daughter cells. Thus, FtsZ needs to be linked to the peptidoglycan synthesis machinery. GpsB is a highly conserved protein among species of the Firmicutes phylum known to regulate peptidoglycan synthesis. Previously, we showed that Staphylococcus aureus GpsB directly binds to FtsZ by recognizing a signature sequence in its C-terminal tail (CTT) region. As the GpsB recognition sequence is also present in Bacillus subtilis, we speculated that GpsB may interact with FtsZ in this organism. Earlier reports revealed that disruption of gpsB and ftsA or gpsB and ezrA is deleterious. Given that both FtsA and EzrA also target the CTT of FtsZ for interaction, we hypothesized that in the absence of other FtsZ partners, GpsB-FtsZ interaction may become apparent. Our data confirm that is the case, and reveal that GpsB interacts with FtsZ in multiple species and stimulates the GTPase activity of the latter. Moreover, it appears that GpsB may serve as an accessory Z-ring anchor such as when FtsA, one of the main anchors, is absent.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar10"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Remodeling of cytoskeleton, chromatin, and gene expression during mechanical rejuvenation of aged human dermal fibroblasts. 衰老人真皮成纤维细胞机械返老还童过程中细胞骨架、染色质和基因表达的重塑。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-12-04 DOI: 10.1091/mbc.E24-09-0430

Trinadha Rao Sornapudi, Luezhen Yuan, Jana M Braunger, Caroline Uhler, G V Shivashankar

{"title":"Remodeling of cytoskeleton, chromatin, and gene expression during mechanical rejuvenation of aged human dermal fibroblasts.","authors":"Trinadha Rao Sornapudi, Luezhen Yuan, Jana M Braunger, Caroline Uhler, G V Shivashankar","doi":"10.1091/mbc.E24-09-0430","DOIUrl":"10.1091/mbc.E24-09-0430","url":null,"abstract":"Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been explored. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood. Here, we studied the cytoskeletal, genome-wide chromatin and transcriptional changes in young, aged, and mechanically rejuvenated fibroblasts using immunofluorescence, RNA sequencing, and Hi-C experiments. The mechanically rejuvenated aged fibroblasts, that had partially reset their transcription to a younger cell state, showed a local reorganization of the interchromosomal contacts and lamina-associated domains. Interestingly, the observed chromatin reorganization correlated with the transcriptional changes. Immunofluorescence experiments in the rejuvenated state confirmed increased actomyosin contractility like younger fibroblasts. In addition, the rejuvenated contractile properties were maintained over multiple cell passages. Overall, our results give an overview of how changes in the cytoskeleton, chromatin, and gene activity are connected to aging and rejuvenation.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar6"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Salmonella-induced cholesterol accumulation in infected macrophages suppresses autophagy via mTORC1 activation. 沙门氏菌诱导的胆固醇在受感染巨噬细胞中积累，通过激活 mTORC1 抑制自噬。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1091/mbc.E24-06-0283

Holly M Torsilieri, Clint M Upchurch, Norbert Leitinger, James E Casanova

{"title":"Salmonella-induced cholesterol accumulation in infected macrophages suppresses autophagy via mTORC1 activation.","authors":"Holly M Torsilieri, Clint M Upchurch, Norbert Leitinger, James E Casanova","doi":"10.1091/mbc.E24-06-0283","DOIUrl":"10.1091/mbc.E24-06-0283","url":null,"abstract":"Salmonella enterica serovar Typhimurium is a Gram-negative bacillus that infects the host intestinal epithelium and resident macrophages. Many intracellular pathogens induce an autophagic response in host cells but have evolved mechanisms to subvert that response. Autophagy is closely linked to cellular cholesterol levels; mTORC1 senses increased cholesterol in lysosomal membranes, leading to its hyperactivity and suppression of autophagy. Previous studies indicate that Salmonella infection induces dramatic accumulation of cholesterol in macrophages, a fraction of which localizes to Salmonella containing vacuoles (SCVs). We previously reported that the bacterial effector protein SseJ triggers cholesterol accumulation through a signaling cascade involving focal adhesion kinase (FAK) and Akt. Here we show that mTORC1 is recruited to SCVs and is hyperactivated in a cholesterol-dependent manner. If cholesterol accumulation is prevented pharmacologically or through mutation of sseJ, autophagy is induced and bacterial survival is attenuated. Notably, the host lipid transfer protein OSBP (oxysterol binding protein 1) is also recruited to SCVs and its activity is necessary for both cholesterol transfer to SCVs and mTORC1 activation during infection. Finally, lipidomic analysis of Salmonella-infected macrophages revealed new insights into how Salmonella may manipulate lipid homeostasis to benefit its survival. We propose that S. Typhimurium induces cholesterol accumulation through SseJ to activate mTORC1, preventing autophagic clearance of bacteria.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar3"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Measurements of neurite extension and nucleokinesis in an iPSC-derived model system following microtubule perturbation. 微管扰动后 iPSC 衍生模型系统中神经元延伸和核运动的测量。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1091/mbc.E24-02-0061

Muriel Sébastien, Alexandra L Paquette, Lilian Ferotin, Adam G Hendricks, Gary J Brouhard

{"title":"Measurements of neurite extension and nucleokinesis in an iPSC-derived model system following microtubule perturbation.","authors":"Muriel Sébastien, Alexandra L Paquette, Lilian Ferotin, Adam G Hendricks, Gary J Brouhard","doi":"10.1091/mbc.E24-02-0061","DOIUrl":"10.1091/mbc.E24-02-0061","url":null,"abstract":"In neurons, patterns of different microtubule types are essential for neurite extension and nucleokinesis. Cellular model systems such as rodent primary cultures and induced pluripotent stem cells (iPSC)-derived neurons have provided key insights into how these patterns are created and maintained through the action of microtubule-associated proteins, motor proteins, and regulatory enzymes. iPSC-derived models show tremendous promise but lack benchmarking and validation relative to rodent primary cultures. Here we have characterized a recent iPSC-derived model, in which doxycycline-induced expression of Neurogenin-2 drives consistent transdifferentiation into the neuronal state (EBiSC-NEUR1 neurons, referred to as NGN2 neurons below). We developed a suite of open-access, semiautomated methods to measure neurite extension and nucleokinesis of NGN2 neurons, which compare favorably to published data from other models. Then, we challenged NGN2 neurons with a panel of drugs that perturb microtubule physiology. NGN2 neurons extension and nucleokinesis were significantly perturbed by two microtubule-targeting drugs, namely a taxane (paclitaxel) and a vinca alkaloid (DZ-2384). In contrast, inhibition of microtubule severing (spastazoline) or of deacetylation (trichostatin A) had a limited effect on nucleokinesis only. Our results support the primary importance of microtubule dynamics in neuronal development and demonstrate the power of NGN2 neurons as a model system.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mr1"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Toxoplasma gondii homolog of ATPase inhibitory factor 1 is critical for mitochondrial cristae maintenance and stress response. 弓形虫 ATPase 抑制因子 1 的同源物对线粒体嵴的维持和应激反应至关重要。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1091/mbc.E24-08-0344

Madelaine M Usey, Anthony A Ruberto, Kaelynn V Parker, Diego Huet

{"title":"The Toxoplasma gondii homolog of ATPase inhibitory factor 1 is critical for mitochondrial cristae maintenance and stress response.","authors":"Madelaine M Usey, Anthony A Ruberto, Kaelynn V Parker, Diego Huet","doi":"10.1091/mbc.E24-08-0344","DOIUrl":"10.1091/mbc.E24-08-0344","url":null,"abstract":"The production of energy in the form of ATP by the mitochondrial ATP synthase must be tightly controlled. One well-conserved form of regulation is mediated via ATPase inhibitory factor 1 (IF1), which governs ATP synthase activity and gene expression patterns through a cytoprotective process known as mitohormesis. In apicomplexans, the processes regulating ATP synthase activity are not fully elucidated. Using the model apicomplexan Toxoplasma gondii, we found that knockout and overexpression of TgIF1, the structural homolog of IF1, significantly affected gene expression. Additionally, TgIF1 overexpression resulted in the formation of a stable TgIF1 oligomer and increased the presence of higher order ATP synthase oligomers. We also show that parasites lacking TgIF1 exhibit reduced mitochondrial cristae density, and that while TgIF1 levels do not affect growth in conventional culture conditions, they are crucial for parasite survival under hypoxia. Interestingly, TgIF1 overexpression enhances recovery from oxidative stress, suggesting a mitohormetic function. In summary, while TgIF1 does not appear to play a role in ATP synthase regulation under conventional growth conditions, our work uncovers its potential role in adapting to the stressors faced by T. gondii and other apicomplexans throughout their intricate life cycles.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar6"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CARMIL1-AA selectively inhibits macropinocytosis while sparing autophagy. CARMIL1-AA 可选择性地抑制大吞噬作用，同时避免自噬。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1091/mbc.E24-09-0434

Rebecca M Lim, Alexa Lu, Brennan M Chuang, Cecily Anaraki, Brandon Chu, Christopher J Halbrook, Aimee L Edinger

{"title":"CARMIL1-AA selectively inhibits macropinocytosis while sparing autophagy.","authors":"Rebecca M Lim, Alexa Lu, Brennan M Chuang, Cecily Anaraki, Brandon Chu, Christopher J Halbrook, Aimee L Edinger","doi":"10.1091/mbc.E24-09-0434","DOIUrl":"10.1091/mbc.E24-09-0434","url":null,"abstract":"Macropinocytosis is reported to fuel tumor growth and drug resistance by allowing cancer cells to scavenge extracellular macromolecules. However, accurately defining the role of macropinocytosis in cancer depends on our ability to selectively block this process. 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) is widely used to inhibit macropinocytosis but affects multiple Na+/H+ exchangers (NHE) that regulate cytoplasmic and organellar pH. Consistent with this, we report that EIPA slows proliferation to a greater extent than can be accounted for by macropinocytosis inhibition and triggers conjugation of ATG8 to single membranes (CASM). Knocking down only NHE1 would not avoid macropinocytosis-independent effects on pH. Moreover, contrary to published reports, NHE1 loss did not block macropinocytosis in multiple cell lines. Knocking down CARMIL1 with CRISPR-Cas9 editing limited macropinocytosis, but only by 50%. In contrast, expressing the CARMIL1-AA mutant inhibits macropinocytosis induced by a wide range of macropinocytic stimuli to a similar extent as EIPA. CARMIL1-AA expression did not inhibit proliferation, highlighting the shortcomings of EIPA as a macropinocytosis inhibitor. Importantly, autophagy, another actin dependent, nutrient-producing process, was not affected by CARMIL1-AA expression. In sum, constitutive or inducible CARMIL1-AA expression reduced macropinocytosis without affecting proliferation, RAC activation, or autophagy, other processes that drive tumor initiation and progression.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar4"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0