Ask about this productRelated genes to: WDR24 antibody
- Gene:
- WDR24 NIH gene
- Name:
- WD repeat domain 24
- Previous symbol:
- C16orf21
- Synonyms:
- DKFZp434F054, JFP7
- Chromosome:
- 16p13.3
- Locus Type:
- gene with protein product
- Date approved:
- 2003-05-08
- Date modifiied:
- 2014-11-19
Related products to: WDR24 antibody
Related articles to: WDR24 antibody
- 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 - The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. ). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. ). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation. - Source: PubMed
Publication date: 2025/08/20
Valenstein Max LWranik MaximilianLalgudi Pranav VLinde-Garelli Karen YChoi YuriChivukula Raghu RSabatini David MRogala Kacper B - Mammalian cells regulate growth by integrating environmental cues through the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The human GATOR2 complex, comprising WDR59, WDR24, Mios, Sec13, and Seh1l, is key to mTORC1 regulation. Under amino acid deprivation, GATOR2 is inhibited through interactions with cytosolic leucine sensor Sestrin2 and arginine sensor cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Amino acid abundance relieves this inhibition, allowing GATOR2 to antagonize the repressor GATOR1. Despite its importance, GATOR2's inhibition mechanisms were unclear. Here, we present cryo-electron microscopy (cryo-EM) structures of GATOR2 in three inhibitory states: CASTOR1 bound, Sestrin2 bound, and dual bound. CASTOR1 engages the Mios WD40 β-propellers, while Sestrin2 interacts with the WDR24-Seh1l subcomplex, inducing conformational movements. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) reveals dynamic motions in apo-GATOR2 and its complexes with amino acid sensors, as well as the effects of amino acid supplementation. These findings unravel the interactions between GATOR2 and amino acid sensors, providing a perspective on the regulation of the mTORC1 pathway by nutrient-sensing machinery. - Source: PubMed
Publication date: 2025/07/30
Su Ming-YuanTeng FeiWang ShanMai XinyiZeng HuanLi JuanSong XiaoxiaoWang XiStjepanovic Goran - Laryngeal cancer (LC), a prevalent malignant tumor of the head and neck, is characterized by a high rate of postoperative recurrence and significant treatment challenges upon recurrence, severely impacting patients' quality of life. There is a pressing need for effective biomarkers in clinical practice to predict the risk of LC recurrence and guide the development of personalized treatment plans. This study uses bioinformatics methods to explore potential biomarkers for LC recurrence, focusing on key genes and exploring their functions and mechanisms of action in LC recurrence. The aim is to provide new perspectives and evidence for clinical diagnosis, prognostic evaluation, and targeted treatment of LC. - Source: PubMed
Publication date: 2024/07/26
Liu LaiyanWu Jiebin - Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8 T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8 T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8 T cells. This decreased T-bet expression and reduced IFN-γ production by CD8 T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity. - Source: PubMed
Publication date: 2024/05/28
Cheng HongyuJi ZheWang YangLi ShenzhiTang TianqiWang FeiPeng ChengWu XiangyangCheng YuannaLiu ZhonghuaMa MingtongWang JieHuang XiaochenWang LinQin LianhuaLiu HaipengChen JianxiaZheng RuijuanFeng Carl GCai XiaQu DiYe LilinYang HuaGe Baoxue