Ask about this productRelated genes to: TUSC4 antibody
- Gene:
- NPRL2 NIH gene
- Name:
- NPR2 like, GATOR1 complex subunit
- Previous symbol:
- TUSC4
- Synonyms:
- NPR2L, NPR2
- Chromosome:
- 3p21.31
- Locus Type:
- gene with protein product
- Date approved:
- 2004-01-20
- Date modifiied:
- 2017-06-13
Related products to: TUSC4 antibody
Related articles to: TUSC4 antibody
- Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5-S127, thereby recruiting the Cullin3 E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8 T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5-pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5-pS127-mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME. - Source: PubMed
Publication date: 2026/04/03
Xiang JunyuWang TaoTian ShuoranLi JinyangLuo MengyunWang YuzhuDu AibeiChen XuTian FanxuanWang LeiZhang YongchaoHan MengyiHou WenqingWang XinyuHou TaoLiu QinChen DongfengWen LiangzhiQin ZhongyiLi XianfengJiang CongZhang QiaoqiaoLiu PengdaBian XiuwuWei WenyiWang Bin - Host factors that directly target viral immune antagonists are crucial for antiviral defense. In this study, we identify NPRL2 as a novel host restriction factor that directly interacts with the porcine reproductive and respiratory syndrome virus (PRRSV) protein Nsp1α, a key viral virulence factor. This interaction is mediated by the C-terminal domain of NPRL2 and the PCPα domain of Nsp1α. Functional studies demonstrated that NPRL2 overexpression inhibits PRRSV replication, while its knockdown enhanced viral propagation. Mechanistically, NPRL2 acts as a bridge, mediating K63-linked ubiquitination of Nsp1α at lysine 150 and subsequently recruiting the autophagic machinery for its degradation. This process was confirmed by monitoring LC3-II conversion and autophagic flux. Our findings reveal a precise mechanism by which NPRL2 antagonizes PRRSV by targeting a critical viral protein for autophagic degradation, highlighting the therapeutic potential of harnessing the host's ubiquitin-autophagy pathway to combat viral infections. - Source: PubMed
Publication date: 2026/02/25
Yi HeyouWang ShaojunWang QiumeiLu LechenXie ErminYe RuiruiWang HengZhang Guihong - Radiotherapy resistance remains a major clinical challenge in colorectal cancer (CRC) treatment. Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity. We identify NPRL2 as the central mediator of this process. Following radiation, NPRL2 rapidly translocates to the nucleus, where it directly binds to the catalytic domains of key E3 ubiquitin ligases, including HERC2 and RNF8, and functionally inactivates them. This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins. Importantly, clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance. Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation. Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation, leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both and models. These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC, but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients. - Source: PubMed
Publication date: 2025/10/31
Wang XuecenZhao YuxuanYang XingliLiu TingyuZhou WeilinNiu ShaoqingJin MengChen YongLiu Ran-YiBao YongYue Xin - mTORC1 coordinates cellular growth and metabolism by integrating inputs from both amino acids and growth factors, and its activation requires two upstream branches involving the Rag GTPases and the Rheb GTPase. These branches are regulated by distinct GAP complexes: GATOR1 (Depdc5-Nprl2-Nprl3) inhibits RagA/B, and TSC (TSC1-TSC2-TBC1D7) inhibits Rheb. Despite the prevailing view that these pathways converge only at mTORC1 itself, several observations suggest upstream crosstalk. This gap is especially striking in organisms like and that lack the TSC complex yet maintain fully responsive mTORC1 signaling. How these inputs are dynamically coordinated under complex physiological conditions and in organisms lacking the key components remain unknown. We performed unbiased quantitative proteomics in and identified the GATOR1 complex as a previously unrecognized RHEB-1 ( ortholog of Rheb) interactor. Through biochemical validation in human cells, we show that nucleotide-free Rheb associates with the Nprl2-Nprl3 subunits of GATOR1, whereas GTP-bound or membrane-detached Rheb mutants fail to bind. Nutrient stress, but not direct pharmacologic inhibition of mTORC1, robustly induced this interaction. In TSC2-null cells, where Rheb is constitutively GTP-loaded, Rheb-Nprl2/3 binding was strongly diminished and was restored by expressing the nucleotide-free Rheb mutant, demonstrating that Rheb's nucleotide state governs this interaction. Pulldown assays confirmed that the Nprl2/3 heterodimer is sufficient for binding nucleotide-free Rheb. Structural modeling using AlphaFold3 consistently positioned Rheb at a conserved site on Nprl3 distinct from the RagA/B GAP-active surface of Nprl2, supporting a non-catalytic mode of association. Together, these findings identify a conserved, nutrient-regulated physical interaction between Rheb and the Nprl2/3 subunits of GATOR1, revealing a previously unrecognized point of convergence between the growth factor and amino acid branches of the mTORC1 pathway. This model provides a direct molecular link between the Rag and Rheb branches, furthering our understanding of how nutrient stress fine-tunes mTORC1 signaling. - Source: PubMed
Publication date: 2025/12/23
Prabhakar AditiMair William B - Cisplatin administration is the primary chemotherapy approach for many epithelial cancers. However, resistance to this drug poses a significant challenge to effective treatment. Despite the identification of numerous factors associated with resistance, reliable biomarkers predicting drug response remain elusive. Previously, low expression of the NPRL2 tumor suppressor was linked to cisplatin resistance. NPRL2, along with NPRL3 and DEPDC5, forms the GATOR1 complex, an upstream regulator of the mTORС1, the function of which is perturbed in many cancers, particularly those resistant to cisplatin. Here, we compare non-cancerous bronchial epithelium BEAS-2B cells with GATOR1 deletions, serving as a model of intrinsic cisplatin resistance, with non-small cell lung cancer lines A549, H460, and H1975 with acquired resistance to the drug. We found that deletion of any GATOR1 member, not solely NPRL2, promotes cisplatin resistance, whereas their overexpression renders cells sensitive to the drug. In cells with GATOR1 deletions, expression of the ATP7A transporter required for cisplatin efflux is increased, while expression of cisplatin influx transporters CTR2 and LRRC8A is downregulated, especially after treatment with the drug. This hinders drug accumulation in cells, resulting in the formation of fewer cisplatin-DNA adducts. Simultaneously, these cells exhibit enhanced DNA damage response and mTORC1 activity. Overexpression of GATOR1 components and/or concomitant treatment with an mTORC1 inhibitor restores sensitivity to cisplatin. Transcriptomic analysis of GATOR1-deleted BEAS-2B cells, treated or not with the drug, identifies new signatures important for understanding GATOR1 function and its role in cisplatin resistance. Thus, GATOR1 not only participates in the cellular response to amino acid availability but also plays a role in resistance to DNA-damaging anticancer drugs. This novel function of GATOR1 should be taken into account when developing new strategies to combat chemoresistance. - Source: PubMed
Publication date: 2025/12/30
Pan ZhenruiZhang HanxiaoXiao XiaBrenner CatherineDokudovskaya Svetlana