Ask about this productRelated genes to: VPS4A Blocking Peptide
- Gene:
- VPS4A NIH gene
- Name:
- vacuolar protein sorting 4 homolog A
- Previous symbol:
- -
- Synonyms:
- VPS4, VPS4-1, FLJ22197, SKD2, SKD1, SKD1A
- Chromosome:
- 16q23.1
- Locus Type:
- gene with protein product
- Date approved:
- 2002-06-12
- Date modifiied:
- 2016-04-05
Related products to: VPS4A Blocking Peptide
Related articles to: VPS4A Blocking Peptide
- Microglia are the resident immune cells of the brain and serve as key regulators of innate immune responses within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that plays a central role in innate immunity, and its excessive activation contributes to the pathogenesis of neurodegenerative diseases. Nilotinib, a second-generation tyrosine kinase inhibitor, has recently attracted attention due to its neuroprotective and immunomodulatory properties in the CNS. In the present study, we investigated the effects of nilotinib on NLRP3 inflammasome activation, GSDMD/NINJ1-mediated pyroptosis, NF-κB signaling, BAG3-dependent aggrephagy, and ESCRT-III-mediated plasma membrane repair in LPS plus ATP-induced murine N9 microglial cells. Our findings demonstrated that nilotinib significantly attenuated NLRP3 inflammasome activation, as evidenced by reduced NLRP3 expression, decreased caspase-1 activation, and suppressed secretion of proinflammatory cytokines IL-1β and IL-18 through modulation of the IκBα/NF-κB signaling axis. Furthermore, nilotinib markedly inhibited pyroptotic cell death by reducing GSDMD-N and NINJ1 expression, thereby preserving membrane integrity. In parallel, nilotinib enhanced BAG3-dependent selective autophagy and increased LC3B expression, suggesting activation of aggrephagy pathways involved in the clearance of inflammasome-associated components. Notably, nilotinib also restored VPS4A expression, indicating activation of ESCRT-III-mediated plasma membrane repair mechanisms. Collectively, our results reveal that nilotinib exerts a multi-layered regulatory effect on microglial inflammatory responses by suppressing inflammasome activation and pyroptosis while promoting autophagy-dependent clearance and membrane repair pathways. These findings highlight a novel integrative mechanism linking autophagy, pyroptosis, and membrane repair in the neuroprotective actions of nilotinib. - Source: PubMed
Publication date: 2026/08/31
Erdem MehmetErdem ŞenizKarahan Süleyman Caner - Cerebellar hypoplasia, impaired intellectual development, congenital microcephaly, dystonia, anemia, and growth retardation (CIMDAG) syndrome is caused by variants in VPS4A. We report a 5-year-old Nepalese boy with classical CIMDAG features, including developmental delay, microcephaly, dystonia, cataracts, dyserythropoietic anemia, and growth retardation. Magnetic resonance imaging showed mild cerebellar atrophy. Trio exome sequencing identified a homozygous VPS4A variant (c.863G>A; p.Arg288Gln), predicted to be deleterious. Structural analyses revealed disruption of a conserved Arginine-288 residue within the ATPases associated with diverse cellular activities domain, leading to loss of stability and increased disorder. The VPS4A-p.Arg288Gln variant showed enhanced aggregation and reduced interaction with LC3B (microtubule-associated protein 1 light chain 3 beta), impairing its localization to lipid droplets. Proband fibroblasts exhibited increased lipid accumulation, elevated free fatty acids, and higher reactive oxygen species levels, indicative of lipotoxic stress. Together, these findings demonstrate that a novel pathogenic VPS4A variant drives structural destabilization and lipotoxicity, providing mechanistic insight into lipid homeostasis perturbations in CIMDAG syndrome. - Source: PubMed
Publication date: 2026/07/09
Gupta ApurvaMathuria Yogendra PratapJain Buddhi PrakashGupta Shailesh KumarGhosh Debasish Kumar - Hepatic stellate cell (HSC) activation is a central driver of liver fibrogenesis. FKBP10, a collagen-associated chaperone involved in extracellular matrix remodeling, has not been fully characterized in liver fibrosis. Here, we investigated the functional role and underlying mechanism of FKBP10 in HSC activation and fibrotic progression. - Source: PubMed
Publication date: 2026/04/22
Zhang JingyuYuan JiahaoCheng WeiTang HanFan XuWang XueLiu LinWang PingLiu TianhuiZhao XinyanCong Min - The AAA+ ATPase VPS4 drives the ESCRT machinery in diverse intracellular membrane remodeling events, including endocytic receptor sorting, membrane repair, and autophagosome closure. Tumor cells often lose one VPS4 paralog (VPS4A or VPS4B), making them dependent on the remaining enzyme and creating a potential therapeutic vulnerability. Inhibiting VPS4 induces cancer cell-autonomous death and may also modulate the immune microenvironment, although the underlying mechanisms remain unclear. Here, we report that VPS4 inhibition triggered upregulation of cytokine and innate immune signaling, along with canonical NF-κB, stress response, and cell death pathways in murine rhabdomyosarcoma (RMS) cells. Pharmacological and genetic analyses identified the cGAS-STING-TBK1-IRF3 axis, activated by cytoplasmic mitochondrial DNA, as the primary driver of cytokine induction. In an orthotopic syngeneic RMS model, VPS4 inhibition suppressed tumor growth while fostering a more immunogenic microenvironment. Although STING was dispensable for VPS4 inhibition-induced RMS cell death, its loss reduced natural killer and dendritic cell infiltration and attenuated the overall anti-tumor effects of VPS4 inhibition. These findings establish a dual role for VPS4 inhibition in inducing tumor cell death and promoting anti-tumor immunity, highlighting the therapeutic potential of targeting VPS4 vulnerability in cancer. - Source: PubMed
Publication date: 2026/04/24
Zhang RayChen LongguiLiang XinwenZhang JiawenHamamoto KoutaHattori TatsuyaVangala VenugopalSchell Todd DSaulnier Sholler GiselleTakahashi YoshinoriWang Hong-Gang - The final step of the Human immunodeficiency virus type 1 (HIV-1) replication cycle, virion budding and scission from the host cell membrane, is executed not by a viral enzyme but by the hijacked host endosomal sorting complexes required for transport (ESCRT) machinery. - Source: PubMed
Publication date: 2026/04/13
Yaseen Mahmoud MAbuharfeil Nizar