American journal of physiology. Cell physiology最新文献

{"title":"CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.","authors":"Guiyin Zhu, Haiyang Yu, Xiaoming Li, Wenjing Ye, Xi Chen, Wen Gu","doi":"10.1152/ajpcell.00735.2024","DOIUrl":"10.1152/ajpcell.00735.2024","url":null,"abstract":"<p><p>CD147 has the potential to serve as a specific target with therapeutic characteristics in several respiratory diseases. Studies have demonstrated that CD147 regulates levels of oxidative phosphorylation (OXPHOS) through the process of mitochondrial translocations. However, there is still limited insight in the distinct mechanism of CD147 in asthmatic macrophages. Here, we found that CD147 expression levels increased significantly both in vivo and in vitro. CD147 undergoes mitochondrial translocation in M2 macrophages. Reducing the expression of CD147 resulted in a decline in M2 polarization levels within macrophages, as well as a decrease in the levels of mitochondrial respiratory chain complexes I, II, and IV proteins. This effect may be attained by interacting with adenine nucleotide translocase 1 (ANT1), subsequently impacting the levels of mitophagy. We also discovered that CD147 knockdown significantly reduced airway remodeling and inflammation in addition to lowering the polarization level of M2 in the lung tissues of chronic asthmatic model mice. The findings represent the first evidence of the distinct function of CD147 in the process of airway remodeling in asthma.<b>NEW & NOTEWORTHY</b> The interaction between CD147 and ANT1 in M2 macrophages occurs via mitochondrial translocation, resulting in alterations in ANT1 expression levels. This, in turn, triggers the activation of the mitophagy pathway, leading to modifications in OXPHOS levels. Ultimately, these changes contribute to the enhancement of M2 polarization, thereby exacerbating airway remodeling in asthma.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C604-C616"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum for Koch and Bűttner, volume 324, 2023, p. C1126-C1140.","authors":"","doi":"10.1152/ajpcell.00487.2022_COR","DOIUrl":"https://doi.org/10.1152/ajpcell.00487.2022_COR","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 2","pages":"C728"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation.","authors":"Christopher J Guerriero, Marcelo D Carattino, Katherine G Sharp, Luke J Kantz, Nikolay P Gresko, Michael J Caplan, Jeffrey L Brodsky","doi":"10.1152/ajpcell.00776.2024","DOIUrl":"10.1152/ajpcell.00776.2024","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder leading to end-stage renal disease. ADPKD arises from mutations in the <i>PKD1</i> and <i>PKD2</i> genes, which encode polycystin 1 (PC1) and polycystin 2 (PC2), respectively. PC2 is a nonselective cation channel, and disease-linked mutations disrupt normal cellular processes, including signaling and fluid secretion. In this study, we investigate whether disease-causing missense mutations compromise PC2 folding, an event that can lead to endoplasmic reticulum-associated degradation (ERAD). To this end, we first developed a new yeast PC2 expression system. We show that the yeast system provides a tractable model to investigate PC2 biogenesis and that a disease-associated PC2 mutant, D511V, exhibits increased polyubiquitination and accelerated proteasome-dependent degradation compared with wild-type PC2. In contrast to wild-type PC2, the PC2 D511V variant also failed to improve the growth of yeast strains that lack endogenous potassium transporters, highlighting a loss of channel function at the cell surface and a new assay for loss-of-function <i>PKD2</i> variants. In HEK293 cells, both D511V along with another disease-associated mutant, R322Q, were targeted for ERAD. Consistent with defects in protein folding, the surface localization of these PC2 variants was increased by incubation at low-temperature in HEK293 cells, underscoring the potential to pharmacologically rescue these and perhaps other misfolded PC2 alleles. Together, our study supports the hypothesis that select PC2 missense variants are degraded by ERAD, the potential for screening <i>PKD2</i> alleles in a new genetic system, and the possibility that chemical chaperone-based therapeutic interventions might be used to treat ADPKD.<b>NEW & NOTEWORTHY</b> This study indicates that select missense mutations in PC2, a protein that when mutated leads to ADPKD, result in protein misfolding and degradation via the ERAD pathway. Our work leveraged a new yeast model and an HEK293 cell model to discover the mechanism underlying PC2 instability and demonstrates the potential for pharmacological rescue. We also suggest that targeting the protein misfolding phenotype with chemical chaperones may offer new therapeutic strategies to manage ADPKD-related protein dysfunction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C483-C499"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescent myoblasts exhibit an altered exometabolome that is linked to senescence-associated secretory phenotype signaling.","authors":"Michael Kamal, Meera Shanmuganathan, Zachery Kroezen, Sophie Joanisse, Philip Britz-McKibbin, Gianni Parise","doi":"10.1152/ajpcell.00880.2024","DOIUrl":"10.1152/ajpcell.00880.2024","url":null,"abstract":"<p><p>Cellular senescence has been implicated in the aging-related dysfunction of satellite cells, the resident muscle stem cell population primarily responsible for the repair of muscle fibers. Despite being in a state of permanent cell cycle arrest, these cells remain metabolically active and release an abundance of factors that can have detrimental effects on the cellular microenvironment. This phenomenon is known as the senescence-associated secretory phenotype (SASP), and its metabolic profile is poorly characterized in senescent muscle. In the present investigation, we examined the intracellular and extracellular metabolome of C₂C₁₂ myoblasts using a bleomycin (BLEO)-mediated model of DNA damage-induced senescence. We also evaluated the relationship between the senescent metabolic phenotype and SASP signaling through molecular and network-based analyses. Senescent myoblasts exhibited a significantly altered extracellular metabolome (i.e., exometabolome), including increased secretion of several aging-associated metabolites. Four of these metabolites-trimethylamine-<i>N</i>-oxide (TMAO), xanthine, choline, and oleic acid-were selected for individual dose-response experiments to determine whether they could drive the senescence phenotype. Although most of the tested metabolites did not independently alter senescence markers, oleic acid treatment of healthy myoblasts significantly upregulated the SASP genes <i>Ccl2</i>, <i>Cxcl12</i>, and <i>Il33</i> (<i>p</i> < 0.05). A gene-metabolite interaction network further revealed that oleic acid was one of the most interconnected metabolites to key senescence-associated genes. Notably, oleic acid interacted with several prominent SASP genes, suggesting a potential epigenetic effect between this monounsaturated fatty acid and SASP regulation. In summary, the exometabolome, particularly oleic acid, is implicated in SASP signaling within senescent myoblasts.<b>NEW & NOTEWORTHY</b> Cellular senescence and its accompanying secretory phenotype [i.e., the senescence-associated secretory phenotype (SASP)] have been linked to the aging-associated dysfunction of skeletal muscle, yet little is known about this phenomenon in satellite cells. We report that senescent myoblasts experience a significantly altered extracellular metabolome primarily characterized by the substantial release of nonesterified fatty acids. Targeted evaluation of several extracellular senescence-associated metabolites reveals a potential epigenetic role for long-chain fatty acids, particularly oleic acid, in regulating SASP-related gene expression.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C440-C451"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MCF7 breast cancer anabolic capacity reduced with CRISPR/Cas9-mediated stable overexpression of DEPTOR.","authors":"J William Deaver, Patrick J Ryan, Colleen L O'Reilly, Selina Uranga, Sara Mata López, Melinda Sheffield-Moore, Peter P Nghiem, Steven E Riechman, James D Fluckey","doi":"10.1152/ajpcell.00682.2023","DOIUrl":"https://doi.org/10.1152/ajpcell.00682.2023","url":null,"abstract":"<p><p>The hyperactivation of mTOR is a significant contributor to the development and progression of a number of human diseases, including a majority of human cancers. Although there have been many scientific and clinical efforts to reduce the impact of mTOR hyperactivation on downstream cellular metabolism, we aimed to mitigate this hyperactivation through a novel targeted gene edit of the intrinsic mTOR inhibitor, DEP domain containing MTOR interacting protein (DEPTOR), in MCF7 human breast cancer cells. Using publicly available bioinformatics tools, we demonstrate that DEPTOR gene expression is low in breast cancers compared with healthy tissues and that DEPTOR expression predicts overall survival, recurrence-free survival, and distant metastasis-free survival in breast cancer patients. We show that a directed overexpression of DEPTOR protein leads to significant alteration of downstream mTORC1 targets and subsequently reduces overall rates of protein synthesis. In addition, treatment of DEPTOR overexpressing cells with small-molecule DEPTOR inhibitor NSC126405 leads to a reversal of this effect, indicating a direct causal mechanism between DEPTOR protein levels and mTORC1 activation.<b>NEW & NOTEWORTHY</b> We identify DEPTOR as a predictor of mortality in breast cancer and show that precision gene editing to restore DEPTOR expression in breast cancer slows cell growth by inhibiting mTOR activity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 2","pages":"C670-C678"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow-derived NGFR-positive dendritic cells regulate arterial remodeling.","authors":"Shinichiro Takashima, Soichiro Usui, Shintaro Matsuura, Chiaki Goten, Oto Inoue, Yusuke Takeda, Kosei Yamaguchi, Daiki Hashimuko, Yusuke Shinjo, Mitsuhiro Sugita, Keisuke Ohtani, Koji Kubota, Yoshio Sakai, Kenji Sakata, Masayuki Takamura","doi":"10.1152/ajpcell.00665.2024","DOIUrl":"10.1152/ajpcell.00665.2024","url":null,"abstract":"<p><p>It has been proposed that bone marrow contributes to the pathogenesis of arteriosclerosis. Nerve growth factor receptor (NGFR) is expressed in bone marrow stromal cells; it is also present in peripheral blood and ischemic coronary arteries. We hypothesized that bone marrow-derived NGFR-positive (NGFR⁺) cells regulate arterial remodeling. We found that human NGFR⁺ mononuclear cells (MNCs) in peripheral blood expressed markers for plasmacytoid dendritic cells (DCs) and were susceptible to apoptosis in response to proNGF secreted by activated arterial smooth muscle cells (SMCs). Bone marrow-specific depletion of NGFR⁺ cells increased neointimal formation following arterial ligation in mice. Bone marrow-derived NGFR⁺ cells accumulated in the neointima and underwent apoptosis. In contrast, in a bone marrow-specific NGFR-knockout model, SMCs occupied the neointima with augmented proliferation. NGFR⁺ cells in the neointima promoted mannose receptor C-type 1-positive anti-inflammatory macrophage accumulation and secreted anti-inflammatory IL-10, thereby inhibiting SMC proliferation in the neointima. In patients with acute coronary syndrome (ACS), NGFR⁺ peripheral MNCs increased after ACS onset. Multiple linear regression analysis showed that an insufficient increase in NGFR⁺ peripheral MNCs in ACS was an adjusted independent risk factor for 9-mo intimal progression of a nontargeted lesion. Taken together, these observations imply that bone marrow-derived NGFR⁺ DCs are suppressors of arteriosclerosis.<b>NEW & NOTEWORTHY</b> We propose a new concept of arterial remodeling after injury in which bone marrow-derived NGFR⁺ dendritic cells inhibit neointimal progression mediated by apoptosis. NGFR⁺ dendritic cells promote anti-inflammatory MRC1⁺ M2 macrophage accumulation and production of interleukin-10, inhibiting smooth muscle cell proliferation within the neointima. In a clinical study, insufficient mobilization of NGFR⁺ peripheral mononuclear cells in acute coronary syndrome was an independent risk factor for 9-mo nontargeted coronary intimal progression.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C414-C428"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of exogenous β-hydroxybutyrate on BDNF signaling, cognition, and amyloid precursor protein processing in humans with T2D and insulin-resistant rodents.","authors":"B J Baranowski, B F Oliveira, K Falkenhain, J P Little, A Mohammad, S M Beaudette, M S Finch, H G Caldwell, H Neudorf, R E K MacPherson, J J Walsh","doi":"10.1152/ajpcell.00867.2024","DOIUrl":"10.1152/ajpcell.00867.2024","url":null,"abstract":"<p><p>People with type 2 diabetes (T2D) have a greater risk of developing neurodegenerative diseases, like Alzheimer's disease, in later life. Exogenous ketone supplements containing the ketone body β-hydroxybutyrate (β-OHB) may be a strategy to protect the brain as β-OHB can support cerebral metabolism and promote neuronal plasticity via expression of brain-derived neurotrophic factor (BDNF). Parallel human (ClinicalTrials.gov ID NCT04194450, ClinicalTrials.gov ID NCT05155410) and rodent trials were conducted to characterize the effect of acute and short-term exogenous ketone supplementation on indices of brain health. First, we aimed to investigate the effect of acute and short-term supplementation of exogenous ketone monoester on circulating BDNF and cognition in adults with T2D. There were no effects of ketone supplementation on plasma BDNF or cognition. Second, we aimed to investigate the mechanistic effects of acute and chronic β-OHB supplementation on cortical BDNF content and recognition memory in C57BL/6J mice with and without insulin resistance. Acutely, β-OHB did not alter recognition memory or BDNF content. Similarly, chronic β-OHB supplementation did not alter recognition memory or BDNF content. Collectively, our data demonstrates that ketone supplementation does not elevate BDNF content in humans or mice. Furthermore, our data does not support the involvement of BDNF in the potential cognitive benefits of β-OHB supplementation.<b>NEW & NOTEWORTHY</b> Ketone supplementation does not alter circulating BDNF levels or cognition in humans with T2D. Acute and chronic ketone supplementation in C57BL/6J mice did not change BDNF protein content or improve recognition memory. Ketone supplementation in C57BL/6J mice positively modulated β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity, providing a potential future therapeutic strategy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C541-C556"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum-associated degradation: a novel therapeutic avenue for ADPKD.","authors":"Biyang Xu, Alexander Staruschenko","doi":"10.1152/ajpcell.00982.2024","DOIUrl":"10.1152/ajpcell.00982.2024","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C574-C575"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP35 promotes breast cancer progression by regulating PFK-1 ubiquitination to mediate glycolysis.","authors":"Weibin Lian, Chengye Hong, Debo Chen, Chuan Wang","doi":"10.1152/ajpcell.00733.2024","DOIUrl":"10.1152/ajpcell.00733.2024","url":null,"abstract":"<p><p>Ubiquitin-specific protease 35 (<i>USP35</i>) was found to be involved in various tumor progression, but its role in breast cancer remains largely unknown. USP35 mRNA and protein expression in breast cancer tissues and cells were evaluated by quantitative real-time PCR and Western blot, respectively. Subsequently, flow cytometry and 5-ethynyl-2'-deoxyuridine labeling were used to evaluate breast cancer cell apoptosis and proliferation. Cellular glycolytic function was analyzed using the Seahorse assay and various kits. Furthermore, co-immunoprecipitation (Co-IP) and immunoprecipitation assays were utilized to validate the deubiquitylation mechanism of USP35. Finally, a subcutaneous human xenograft tumor model was established in nude mice to verify the effect of USP35 in vivo. By examining the clinical samples and cell lines, we found that USP35 expression was significantly upregulated in breast cancer. Further functional studies showed that knockdown USP35 expression inhibited cell proliferation and promoted apoptosis. In addition, knockdown of USP35 decreased phosphofructokinase1 (PFK-1) expression and was associated with lower extracellular acidification rate and oxygen consumption rate compared with sh-Control. Co-IP assays identified PFK-1 as a direct deubiquitiation target of USP35. Importantly, we demonstrated that PFK-1 is an essential mediator for USP35-induced cell proliferation and glycolysis in vitro and in vivo. This study identified that USP35 regulates the proliferation and glycolysis of breast cancer cells by mediating the ubiquitination level of PFK-1. The USP35/PFK-1 axis offers novel insight for the treatment of breast cancer.<b>NEW & NOTEWORTHY</b> This study identified that USP35 regulates the proliferation and glycolysis of breast cancer cells by mediating the ubiquitination level of PFK-1. The USP35/PFK-1 axis offers novel insight for the treatment of breast cancer.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C355-C366"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HOXA3 activates USP15 to suppress autophagy and promote M2-type macrophage polarization in renal cell carcinoma via facilitating the deubiquitination of SQSTM1.","authors":"Huihuang Li, Yang Li, Zhiyong Chen, Cheng He","doi":"10.1152/ajpcell.00712.2024","DOIUrl":"10.1152/ajpcell.00712.2024","url":null,"abstract":"<p><p>The disease burden of renal cell carcinoma (RCC) has decreased in recent years with advances in treatment, but its pathogeny still remains elusive. We aim to study the role of homeobox A3 (HOXA3)/ubiquitin-specific peptidase 15 (USP15)/SQSTM1 axis on autophagy and M2-type macrophage polarization in RCC. In this study, cell apoptosis and proliferation were assessed by flow cytometry and CCK-8. Autolysosome fusion was observed by immunofluorescence detection of LC3 and LAMP2. The binding between HOXA3 and USP15 promoter was tested by chromatin immunoprecipitation (ChIP), EMSA, and dual-luciferase reporter assays. Also, the interaction between deubiquitinated enzyme (DUB) USP15 and SQSTM1, and ubiquitinated level of SQSTM1 were determined by co-immunoprecipitation (Co-IP) assay. Expression levels of HOXA3, USP15, C-C motif chemokine 2 (CCL2), CCL2 receptor (CCR2), M2-type macrophages, and autophagy-related markers were measured by Western blot, quantitative reverse transcription PCR (RT-qPCR), ELISA, and immunohistochemistry. Role of HOXA3/USP15 axis was verified by xenograft tumor experiment in vivo. We showed upregulated HOXA3 in RCC tissues and cells, and RCC tissues with metastasis showed higher HOXA3 level. The higher HOXA3 expression was relevant to worse overall survival in patients with RCC. HOXA3 induced RCC cell proliferation, and suppressed autophagy and apoptosis via transcriptionally activating USP15 expression. USP15 then induced deubiquitination modification of SQSTM1 in RCC cells. SQSTM1 supported M2-type macrophage polarization by inducing CCL2 secretion. HOXA3 or USP15 knockdown suppressed tumor growth and M2-type macrophage infiltration in vivo. In conclusion, HOXA3 transcriptionally activates USP15 expression, and upregulated USP15 facilitates the deubiquitination of SQSTM1 in RCC. This process on the one hand suppresses autophagy, on the other hand increases M2-type macrophage polarization through stimulating the secretion of CCL2.<b>NEW & NOTEWORTHY</b> We report a novel finding that highly expressed homeobox A3 (HOXA3) transcriptionally activates the expression of ubiquitin-specific peptidase 15 (USP15), resulting in the promotion of deubiquitination of SQSTM1. This process on the one hand suppresses autophagy in renal cell carcinoma (RCC), on the other hand increases M2-type macrophage polarization in the tumor microenvironment through stimulating the secretion of C-C motif chemokine 2 (CCL2).</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C576-C594"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}