Microorganisms
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2025
·Vol. 13
·期 8
·1865
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IF 4.2
Chenchen Zhao,Yan Qin,Haixin Huang,Yuying Li,Xinyu Zhang,Lin Zhou,Lulu Xie,Yimin Zhou,Yanqing Hu,Wei Chen,Tian Lan,Wen-Chao Sun
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a recently discovered enteric coronavirus that has caused considerable economic losses in the pig industry. SADS-CoV was first reported in 2017 in Guangdong Province, China, and subsequently in Fujian, Guangxi, Henan and Jiangxi Provinces. Bone marrow stromal cell antigen 2 (BST-2), also known as tetherin, acts as an antiviral protein to limit the release of a wide range of enveloped viruses. However, the relationship between BST-2 and SADS-CoV has rarely been studied. Here, we showed that endogenous BST-2 expression is downregulated by SADS-CoV infection in Vero-E6 and ST cells by 2- to 3-fold. The overexpression of BST-2 inhibited SADS-CoV replication, whereas the knockdown of the BST-2 gene in Vero cells restored SADS-CoV replication. Further study revealed that BST-2 targets the SADS-CoV nucleocapsid protein (N) and decreases N protein expression, and that the BST-2 transmembrane (TM) domain is essential for this activity. Moreover, the degradation of the SADS-CoV N protein promoted by BST-2 is mediated by the membrane-associated ring-CH-type finger 8 (MARCHF8)/calcium binding and coiled-coil domain 2 (NDP52) autophagosome pathway. Overall, we found that BST-2 suppresses viral proliferation by inducing the breakdown of the SADS-CoV N protein via the MARCHF8/NDP52 pathway.
研究领域:
病毒学
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分子生物学
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免疫学
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细胞生物学
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微生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Xinyi Song,Haipeng Rao,Chunchun Huang,Miaoling Huang,Ying Ma,Jingyu Xin,Jiajia Hou,Zhigang Hu,Lingfeng He,Feiyan Pan,Lingdong Yang,Zhigang Guo
Fumarate hydratase (FH) catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle. Its deficiency leads to fumarate accumulation, which is associated with kidney cancer metastasis, though the exact mechanisms remain unclear. Here, we identify prolyl 4-hydroxylase beta (P4HB) as a novel fumarate target in FH-deficient cancer cells that promotes migration and invasion. FH knockdown in human renal cancer cells significantly enhanced migratory and invasive capacities by 10- and 8-fold, respectively. Mechanistically, fumarate-induced succination stabilizes P4HB, promoting type I collagen production and enhancing tumor metastasis. P4HB knockdown markedly suppresses FH deficiency-induced metastasis in xenograft models. Fluorescence intensity in the FH knockdown group was about 10-fold higher, and tumor-bearing liver weight was approximately 1.5-fold greater than that in the FH and P4HB co-knockdown group. These results underscore the pivotal role of P4HB in metastasis. Additionally, we reveal NDP52 as a specific autophagy receptor that recognizes and binds to P4HB, mediating its degradation through the autophagy-lysosome pathway. However, succination of P4HB disrupts this recognition, interaction, and degradation, stabilizing P4HB. Together, these findings provide new insights into how fumarate-mediated succination affects P4HB protein stability and cancer metastasis, and suggest that P4HB could serve as a potential therapeutic target in FH-deficient cancers.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Veterinary Sciences
·
2025
·Vol. 12
·期 3
·257
·
IF 2.3
Chenchen Zhao,Yan Qin,Haixin Huang,Wei Chen,Yanqing Hu,Xinyu Zhang,Yuying Li,Tian Lan,Wenchao Sun
Simple SummarySADS-CoV is a newly emerging coronavirus affecting the swine industry worldwide. However, our understanding of its pathogenic pathways remains limited. In this study, the researchers aimed to determine the role of the host factor, poly(A)-binding protein 4 (PABPC4), in SADS-CoV infection. This study found that PABPC4 inhibits SADS-CoV replication by degrading the nucleocapsid protein through selective autophagy. This discovery could potentially contribute to developing novel antiviral strategies to prevent and control SADS-CoV infections, protecting the pig industry from significant economic losses.Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important mechanism of host defense against virus invasion. However, the mechanism through which SADS-CoV-mediated selective autophagy mediates the innate immune response remains unknown. Here, we report that the host protein PABPC4 can inhibit SADS-CoV replication through targeting and degrading its N protein. Furthermore, we demonstrate that PABPC4 recruits MARCHF8 (an E3 ubiquitin ligase), which ubiquitinates the N protein and is degraded via NDP52/CALCOCO2 (a selective autophagy cargo receptor). Taken together, these findings reveal a new mechanism by which PABPC4 inhibits virus replication, and reveal a new target for antiviral drug development.
研究领域:
病毒学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2025
·
IF 15.4
Zeng Ke,Zhu Yuqi,Han Zhongxin,Xiong Siyi,Zhao Yan,Xiao Zilong,Xie Yingchao,Jin Shiyu,Dong Tingru,Lan Lan,Liu Weiwei,Du Yongzhong,Guan Cuiping,Yu Xiao,Song Xiuzu
NLRP3 functions as a critical intracellular danger sensor for inflammasome activation, playing a crucial role in autoimmune diseases. Vitiligo progression has been linked to NLRP3, yet its specific involvement in melanocytes of vitiligo remains poorly understood. In this study, we demonstrate that NLRP3 expression is significantly upregulated in the melanocytes of vitiligo patients and melanoma-Treg-induced vitiligo mouse model. Genetic knockout of NLRP3 effectively alleviates vitiligo progression in these mice. Our mechanistic investigations reveal that the downregulation of the E3 ligase β-TrCP1 in vitiligo melanocytes decreases K27-linked ubiquitination levels of NLRP3, which in turn weakens its interaction with the autophagy receptor NDP52. This disruption impairs the selective autophagic degradation of NLRP3, leading to hyperactivation of inflammation and pyroptosis in melanocytes, thereby accelerating vitiligo pathogenesis. Notably, melanocyte-specific knockdown of NLRP3 using lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos) carrying Nlrp3 shRNA significantly alleviates vitiligo development. This study elucidates the mechanism by which autophagy dysfunction mediated excessive NLRP3 inflammasome activation in melanocytes contributes to vitiligo pathogenesis, highlighting potential therapeutic strategies targeting these pathways for the treatment of vitiligo and other pigment-related skin diseases. Overview of disrupted NLRP3 autophagic degradation in vitiligo melanocytes . In healthy melanocytes, NLRP3 expression is upregulated when subjected to oxidative stress, along with an increase in the E3 ligase β-TrCP1, which enhances the K27-linked ubiquitination of NLRP3 and further strengthens its binding to the autophagy receptor protein NDP52, thus effectively suppressing the excessive inflammatory response. Whereas in the melanocytes of vitiligo patients, decreased expression of β-TrCP1 leads to downregulation of K27-linked ubiquitination in NLRP3, thus inhibiting its autophagic degradation. The persistent activation of NLRP3 in vitiligo melanocytes promotes the cleavage of pro-IL-1β and GSDMD. GSDMD-N subsequently forms pores on the cell membrane, which causes the release of IL-1β and results in melanocyte pyroptosis. In our study, we utilize KPV-Lipos with Nlrp3 shRNA to precisely knockdown NLRP3 expression in melanocytes and effectively alleviate vitiligo development, which provide a potentially promising strategy for the treatment of vitiligo. MC, melanocytes.
研究领域:
皮肤病学
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免疫学
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细胞生物学
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自身免疫性疾病
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）