====== Nucleic acid-mediated signaling ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1j1APu8_waJckZBL0yz1xaSOpN3n0gVWhMufO7izndq8dZ8gNT/?limit=15&utm_campaign=pubmed-2&fc=20250326004817}}

**[[Nucleic acid]]-mediated [[signalling]]** refers to cellular [[signaling pathway]]s that are triggered by **[[DNA]] or [[RNA]] molecules**, especially when these nucleic acids are found in unusual locations or come from foreign sources (like [[virus]]es or damaged cells). These molecules serve as **danger signals**, activating the [[immune system]] or [[stress]] responses.


This type of signaling plays a **critical role in innate immunity**, allowing cells to detect infections, cancer, or tissue damage. It's also involved in **[[autoimmune disease]]s**, where the [[immune system]] mistakenly reacts to the body's nucleic acids.

===== 🧪 Key Sensors and Pathways =====


1. **[[Toll-like receptor]]s (TLRs)**

- **[[TLR3]]**: detects double-stranded RNA (dsRNA)

- **TLR7/8**: detect single-stranded RNA (ssRNA)

- **TLR9**: detects unmethylated CpG DNA (common in bacteria/viruses)

2. **RIG-I-like receptors (RLRs)**

- **RIG-I** and **MDA5**: detect viral RNA in the cytosol
- Trigger antiviral responses via **type I interferons**

3. **cGAS-STING pathway**

- **cGAS** detects cytosolic DNA

- Activates **STING**, leading to production of **interferons and inflammatory cytokines**

4. **AIM2 [[inflammasome]]**

- Binds cytosolic DNA

- Triggers **inflammation** through caspase-1 and IL-1β production

===== ⚠️ Clinical Relevance =====

- **Viral infections** (e.g., influenza, COVID-19)

- **Cancer** (cells release DNA into cytosol → immune detection)

- **Autoimmune diseases** (e.g., lupus: response to self-DNA/RNA)

- **Therapeutic targets** (STING agonists in cancer immunotherapy)
----
Nucleic acid-mediated [[signaling]] triggers an immune response that is believed to be central to the [[pathophysiology]] of autoimmunity in [[systemic lupus erythematosus]] (SLE).
Chen et al. found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody enters cells through a nucleoside salvage-linked pathway of membrane transit that avoids [[endosome]]s and [[lysosome]]s and is bound to endogenous RNA in live cells. In [[orthotopic]] models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on [[T cell]]s. Mechanistic studies revealed that antibody binding to [[nucleic acid]]s activated the cytoplasmic pattern recognition receptor cyclic [[GMP]]-[[AMP]] synthase (cGAS), stimulating immune signaling and cGAS-dependent [[cytotoxicity]]. Moreover, the autoantibody could carry and deliver functional RNA into the tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody-nucleic acid interaction that is translatable to strategies for nonviral gene delivery and [[immunotherapy]]
((Chen X, Tang X, Xie Y, Cuffari BJ, Tang C, Cao F, Gao X, Meng Z, Noble PW, Young MR, Turk OM, Shirali A, Gera J, Nishimura RN, Zhou J, Hansen JE. A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells. Sci Signal. 2025 Mar 25;18(879):eadk3320. doi: 10.1126/scisignal.adk3320. Epub 2025 Mar 25. PMID: 40132052.)).
----
Chen et al. deliver a conceptually bold and technically strong paper that bridges [[autoimmunity]], [[cancer immunology]], and [[gene delivery]]. While safety and specificity concerns remain, their discovery of a naturally evolved intracellular delivery vehicle opens new avenues for nonviral [[gene therapy]] and [[immune activation]] strategies.

High novelty, solid mechanistic insight, and strong translational potential, pending validation of safety and delivery scope.