LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity

Cell Reports, Journal Year: 2022, Volume and Issue: 39(9), P. 110880 - 110880

Published: May 1, 2022

Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons drive immune responses against tumors pathogens. Exogenous cGAMP produced by infected malignant cells synthetic used in immunotherapy must traverse the cell membrane activate STING target cells. However, as an anionic hydrophilic molecule, is not inherently permeable. Here, we show that LL-37, a human host defense peptide, can function transporter cGAMP. LL-37 specifically efficiently delivers into transferred robust antiviral immunity STING-dependent manner. Furthermore, report inducers vitamin D3 sodium butyrate promote enhancing endogenous expression its mediated response. Collectively, our data uncover essential role innate activation suggest new strategies for immunotherapy.

Language: Английский

---

Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis

Neuron, Journal Year: 2022, Volume and Issue: 111(2), P. 236 - 255.e7

Published: Nov. 11, 2022

The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote after injury, independent mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator interferon genes (STINGs) activation functional downstream signaling. Directly activating STING by promotes regeneration. In contrast central axons, IFNγ locally translated injured peripheral axons and upregulates cGAS expression Schwann infiltrating blood produce cGAMP, which spontaneous as an immunotransmitter. Our study demonstrates nervous system (PNS) can direct environmental response self-repair antiviral be harnessed (CNS).

Language: Английский

---

ENPP1 Immunobiology as a Therapeutic Target

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(12), P. 2184 - 2193

Published: Jan. 31, 2023

ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides an array physiologic processes. However, is frequently overexpressed local relapses and tumor metastases, which are associated with poor prognosis survival a range solid tumors. promotes immunosuppressive microenvironment (TME) by tilting balance ATP/adenosine (Ado) conjunction other components (CD38, CD39/ENTPD1, CD73/NT5E). Moreover, intersects stimulator interferon genes (STING), impairing its robust immune response through effector 2´,3´-cyclic GMP-AMP. Thus, blockade emerges as unique target eliciting remodeling leveraging STING pathway. Several inhibitors have shown immunostimulatory effect, their combination therapeutic modalities, such immune-checkpoint blockade, activation, DNA damage (DDR) inhibitors, radiotherapy (RT), represents promising avenue to boost antitumor-immune responses improve current clinical outcomes several This comprehensive review summarizes state art opens new perspectives for novel treatment strategies.

Language: Английский

---

Upregulation of LRRC8A by m⁵C modification-mediated mRNA stability suppresses apoptosis and facilitates tumorigenesis in cervical cancer

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(2), P. 691 - 704

Published: Jan. 1, 2023

Cervical cancer (CC) is one of the most common gynecological malignancies with poor prognosis for advanced CC patients. LRRC8A a volume-regulated anion channel protein involved in cellular homeostasis, but its role remains largely unknown. In this study, we found that elevated and associated prognosis. maintains cell survivals under hypotonic condition, promotes tumorigenesis through apoptosis suppression vitro vivo. Notably, upregulated by NSUN2-mediated m5C modification. modified-LRRC8A mRNA bound RNA binding YBX1 followed increased stability. Moreover, loss NSUN2 suppresses proliferation metastasis cells, expression positively correlated CC. Altogether, our study demonstrates NSUN2-m5C-LRRC8A axis crucial would be potential therapeutic target

Language: Английский

---

Structural basis for assembly and lipid-mediated gating of LRRC8A:C volume-regulated anion channels

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(6), P. 841 - 852

Published: March 16, 2023

Language: Английский

---