Cell Res: Finally figured it out! Kang Tiebang et al. of Sun Yat-sen University discovered the underlying mechanism of activated STING in intercellular metastasis to promote anti-tumor immunity

STING is an endoplasmic reticulum (ER) transmembrane protein that mediates innate immune activation stimulated by cGAMP and degraded
by autophagy.

On October 24, 2022, the joint communication of Kang Tiebang and Wei Denghui of Sun Yat-sen University was published online at Cell Research Research paper "Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity," which reports on activated STING Can be transferred between cells to promote anti-tumor immunity, a process triggered by RAB22A-mediated atypical autophagy
.
Mechanically, RAB22A combines with PI4K2A to produce PI4P, and PI4P recruits the Atg12-Atg5-Atg16L1 complex and induces it ER-derived RAB22A mediates atypical autophagosome formation with encapsulated agonist or chemoradiotherapy-activated STING
.
This RAB22A-induced autophagosome fuses with RAB22A-positive early endosomes to produce a new organelle that the researchers call Rafesome (RAB22A-mediated fusion of non-canonical autophagosomes with early endosomes )
。

At the same time, RAB22A inactivates RAB7 and inhibits the fusion of Rafesome with lysosomes, so that autophagic vesicles with activated STING are secreted into a new extracellular vesicle, The study defined it as R-EV (RAB22A-induced extracellular vesicles).

Activated STING-containing R-EV induces the release of IFNβ from recipient cells into the tumor microenvironment, promoting anti-tumor immunity
.
RAB22A can enhance the antitumor effect of the STING agonist diABZI in mice, and high RAB22A levels predict good survival in patients with chemoradiotherapy for nasopharyngeal carcinoma
。 Together, the results of this study reveal that Rafeesome regulates intercellular metastasis of activated STING to trigger and propagate antitumor immunity (ER-derived atypical autophagy vesicle secretion as R-EV ), which provides a new perspective
for understanding the cell-to-cell communication of organelle membrane proteins.

The cGAS-STING signaling pathway plays an important role
in innate immunity.
STING is an endoplasmic reticulum (ER) transmembrane protein activated by cGAMP, a natural ligand produced by cGAS, and recruited by cGAMP TANK-Binding kinase 1 (TBK1), which activates interferon regulator 3 (IRF3)
by phosphorylation.
This pathway induces the production of various cytokines, including type I interferons (IFNs).

The STING pathway has recently become a key regulator of cancer immunity and has been explored
as a potential therapeutic target.
STING agonists or cGAMP have a strong antitumor effect in vivo, but preclinical and clinical data show that STING agonists have a limited
role in systemic administration.

In fact, cGAMP produced by tumor cells can be transferred to NK cells in the tumor microenvironment, activating STING in these NK cells to perform anti-tumor immunity.

However, cGAMP is highly unstable because it can be hydrolyzed by exonucleotide pyrophosphatase/phosphodiesterase, resulting in poor
therapeutic activity.
Therefore, how to better use the STING pathway as a therapeutic target remains a challenge
.

Activated STING has been reported to transmit downstream signals and be degraded
by autophagy.
ER-resident proteins without signaling peptides are generally considered non-secreted proteins, and they are often used as markers of exosome rejection
.
Therefore, whether STING can be transported to extracellular vesicles (EVs) is a puzzling question
.

EVs are found in biological fluids and play a role in cell-to-cell communication, enabling cells to exchange proteins, lipids, genetic material, amino acids, and metabolites
.
EVs are heterogeneous cell-derived membrane structures consisting mainly of exosomes and microvesicles (MVs) derived from the endosomal system and shed
from the plasma membrane, respectively.
Therefore, exosomes and MVs are well documented to contain many cell membrane proteins
.
During the maturation of endosomes into multivesicular endosomes (MVEs), exosomes form intraluminal vesicles (ILVs) in their lumen, and are secreted
by fusion of multivesicular endosomes with the plasma membrane.
ILVs formed by inward budding of MVEs are mainly mediated by the mechanism of Syntenin-Alix-ESCRT-III or RAB31-FLOTs
。

Classic autophagy is a highly conserved process of self-digestion of cellular components that is essential for intracellular homeostasis and adaptive stress, and plays an important role
in various physiological and pathological processes through selective or non-selective degradation of substrates, including protein aggregates, damaged mitochondria, endoplasmic reticulum, lipid droplets, and intracellular pathogens.
The conserved mechanism of classical autophagosome formation consists of two main starting complexes: the ULK1 complex and the class III PI3-kinase complex I that produces PI3P; PI3P production is an important early event
in typical autophagy initiation.

Article pattern diagram (image from Cell Research).

However, there is growing evidence to support the existence of non-canonical autophagy, characterized by the shared use of autophagy mechanisms and the different components working
in multiple different scenarios.
Over the past decade, reports of non-canonical autophagy have not technically involved "self-eating.
"
One of the atypical autophagy processes is named secretory autophagy, which promotes the unconventional secretion
of cytosolic substances such as Acb1, IL-1β, and lysozyme.

In this report, a new organelle, Rafesome (RAB22A-mediated atypical autophagosome fusion with early endosomes), was discovered, and activated STING was found to be packaged into this autophagosome, and in a novel EV Secreted as cargo, R-EV (RAB22A-induced extracellular vesicles).

In conclusion, the study found that Rafeesome regulates intercellular metastasis that activates STING, and activated STING-containing ER induces antitumor immunity in recipient cells
。

Reference Message: