Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation

Shi, Chengyu; Wang, Ying; Wu, Minjie; Chen, Yu; Liu, Fangzhou; Shen, Zheyuan; Xie, Shengling; Shen, Yingying; Sang, Lingjie; Zhang, Zhen; Gao, Zerui; Yang, Luo-jia; Qu, Lei; Yang, Zuozhen; He, Xinyu; Guo, Yu; Pan, Chenghao; Che, Jinxin; Liu, J.; Cai, Zhijian; Yan, Qingfeng; Yu, Luyang; Wang, Liang-jing; Dong, Xiaowu; Xu, Pinglong; Shao, Jian‐Zhong; Liu, Yang; Li, Xu; Wang, Wenqi; Zhou, Ruhong; Zhou, Tian

doi:10.1038/s41467-022-34346-x

Cited by 26 publications

(15 citation statements)

References 55 publications

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“…39 Recent studies indicate that TMUB1 greatly facilitates antitumor immunity and inhibits tumor growth in mice, and it can serve as a potential candidate target to improve the prognosis of cancer-immune patients. 40 Our study demonstrated that TMUB1 knockdown blocked embryo loss and inhibited LPSinduced inflammation and apoptosis. These findings indicate abnormal expression of TMUB1 is tightly linked to a series of illnesses and highlight the potential significance of TMUB1 as a biological marker.…”

Section: Discussionmentioning

confidence: 54%

“…TMUB1 is demonstrated to inhibit the proliferation of rat liver cells and negatively modulate liver regeneration 39 . Recent studies indicate that TMUB1 greatly facilitates antitumor immunity and inhibits tumor growth in mice, and it can serve as a potential candidate target to improve the prognosis of cancer‐immune patients 40 . Our study demonstrated that TMUB1 knockdown blocked embryo loss and inhibited LPS‐induced inflammation and apoptosis.…”

Section: Discussionmentioning

confidence: 57%

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Inhibition of TMUB1 blocks apoptosis and NF‐κB pathway‐mediated inflammation in recurrent spontaneous abortion

Zhang¹,

Zhang³

et al. 2023

Immunity Inflam & Disease

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Introduction Approximately 50% of cases with recurrent spontaneous abortion (RSA) have unexplained etiology. Aberrant expression of transmembrane and ubiquitin‐like domain containing 1 (TMUB1) is closely related to a series of diseases, including RSA. However, the function and underlying mechanism of TMUB1 in the occurrence of RSA has not been described. Methods TMUB1 expression was detected in the placental villous tissues of 30 women with normal miscarriages and 12 women with RSA. The pregnant mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce abortion. Human chorionic trophoblast cells were treated with LPS. Pathological analysis of placental tissues was performed by hematoxylin and eosin staining. Results TMUB1 was highly expressed in the placental villous tissues of RSA patients compared to the patients who underwent induced abortions. After LPS administration, the mice exhibited high embryo absorption and pathological alterations, as well as presented an increase in inflammation and apoptosis (the etiology of RSA induction) in placental tissues. Moreover, the upregulated expression of TMUB1 was also found in placental tissues of LPS‐induced mice, and further investigation showed that TMUB1 deficiency blocked embryo loss as well as inhibited apoptotic rate and inflammation after LPS activation. Furthermore, we found that the loss of TMUB1 suppressed the phosphorylation of IkappaB kinase (IKK) α/β and attenuated cytoplasmic‐nuclear translocation of nuclear factor‐κB (NF‐κB) p65 in LPS‐induced cells. Conclusion Our results indicate that TMUB1 may involve in the modulation of apoptosis and NF‐κB pathway‐mediated inflammation in RSA. Therefore, TMUB1 may develop as a potential biomarker for RSA treatment.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 57%

Inhibition of TMUB1 blocks apoptosis and NF‐κB pathway‐mediated inflammation in recurrent spontaneous abortion

Zhang¹,

Zhang³

et al. 2023

Immunity Inflam & Disease

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“…It has been revealed that PD-L1 is predominantly degraded through two distinct pathways: proteasome and lysosome. Several studies have explored the regulation of PD-L1 proteasomal degradation, with some insights indicating that inhibiting PD-L1 glycosylation or deubiquitination promotes PD-L1 degradation via proteasomes 30 , 34 , 35 . Other research has suggested that HIP1R targets PD-L1 to lysosomal degradation and alters T cell-mediated cytotoxicity 36 .…”

Section: Discussionmentioning

confidence: 99%

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation

Xu,

Xie,

Zhou

et al. 2024

Nat Commun

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Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

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“…There has been a plethora of treatments based on targeting various proteins in cells to trigger anti-tumor immunity over the years. 69, 70 Here, we discovered an unprecedented mechanism in which depleting hnRNPM can elevate antiviral signaling in tumors via cryptic exon-derived long stem-like dsRNAs, triggering a type I interferon response. Such immunity-enhancing properties of hnRNPM-regulated cryptic exons possess vast clinical potential and may expand horizons of treatment for diseases other than cancer.…”

Section: Discussionmentioning

confidence: 99%

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

Zheng

Dunlap

Lyu

et al. 2023

Preprint

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RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

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Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation

Cited by 26 publications

References 55 publications

Inhibition of TMUB1 blocks apoptosis and NF‐κB pathway‐mediated inflammation in recurrent spontaneous abortion

Inhibition of TMUB1 blocks apoptosis and NF‐κB pathway‐mediated inflammation in recurrent spontaneous abortion

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

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