data are presented as mean ± sd, with sem shown for graphical error bars. statistical methods for scrna - seq and spatial analyses are described separately. use of human tissue was approved by nhs blood & transplant ( nhsbt ), the national research ethics committee in the uk ( 21 / wa / 0388, nc. 2018. 010, nc. 2018. 007, rec 16 / ee / 0014 ), and the royal free london nhs foundation trust - ucl biobank ethical review committee ( rfl b - erc / b - erc - rf, nc. 2018. 010; iras 208955 ). written informed consent for research use of donated organs was obtained via nhsbt. ethical approvals for public datasets are detailed in the original studies. raw sequencing data for the 5 new human kidney scrna - seq samples have been made publicly accessible via the european genome - phenome archive ( accession egad00001015631 ). processed seurat and h5ad files are available at zenodo ( https: / / doi. org / 10. 5281 / zenodo. 7566982 ). code for data analysis is available at github ( https: / / github. com / daniyal - jafree1995 / ). imaging data are available upon reasonable request. all raw data used to plot graphs, except for scrna - seq analyses, are provided within the supporting data values file. full experimental details are provided in the supplemental methods, including reagents and protocols, in addition to the steps involved in computational analysis. the role of ma rna methylation of self non - coding rna remains poorly understood. here we show that ma - methylated self u6 snrna is recognized by ythdf2 to reduce its stability and prevent its binding to toll - like receptor 3 ( tlr3 ), leading to decreased inflammatory responses in human and mouse cells and mouse models. at the molecular level, endosomal u6 snrna binds to the lrr21 domain in tlr3, independent of ma methylation, to activate inflammatory gene expression, a mechanism that is distinc t from that of the best known synthetic tlr3 agonist poly i: c. both u6 snrna and ythdf2 are localized to endosomes via the transmembrane protein sidt2, where ythdf2 functions to prevent the u6 - tlr3 interaction. we further show that uvb exposure inhibits ythdf2 by inducing its dephosphorylation and autophagic protein degradation in human keratinocytes and mouse skin. skin - specific deletion of ythdf2 in mice enhanced the uvb - induced skin inflammatory response and promoted tumor initiation. taken together, our findings demonstrate that ythdf2 plays a crucial role in controlling inflammation by inhibiting ma u6 - mediated tlr3 activation, suggesting that ythdf2 and ma u6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis. n - methyladenosine ( ma ) rna methylation is the most prevalent internal modification that occurs in messenger rna ( mrna ) and long non - coding rna ( lncrna ) of most eukaryotes. ma mrna methylation regulates several aspects of rna metabolism, including rna decay, nuclear processing, translation, transcription, and rna - protein interactions. at the molecular level, ma rna modification is installed by writer complexes compose d of factors including mettl3, mettl14, wtap, and kiaa1429, or mettl16, and is removed by erasers fto or alkbh5. ma is recognized by ma - binding proteins including ythdf1 - 3, ythdc1, ythdc1 - 2, and igf2bp1 - 3, also known as ma readers, to regulate rna fate. among the ma writers, mettl16 is monomeric, and is distinc t from mettl3 / mettl14, which is an obligate heterodimer. the mettl16 ortholog mett - 10 in c. elegans has been shown to deposit ma on sam synthase to inhibit its proper splicing. recent studies have demonstrated critical roles for mettl16 in the pathogenesis of leukemia and liver cancer in both ma - dependent and - independent mechanisms. however, the function of mettl16 remains incompletely understood. one ma - modified non - coding rna is the small nuclear rna ( snrna ) u6. u6 snrna is a non - coding rna best known for its role in splicing. u6 interacts with three snrnas, pre - mrna substrates, and more than 25 protein partners to form the catalytic core of the spliceosome during splicing. although commonly used as an internal standard to quantify the level of mirna, u6 snrna was recently recognized as a highly variably expressed gene in various human tissues including carcinoma tissues. notably, u6 snrna levels are significantly higher in human carcinoma tissue than in the corresponding normal tissue. newly synthesized u6 appears transiently in the cytoplasm and undergoes maturation where it is accompanied by u6 - associated proteins known as small nuclear ribonucleoprotein complexes, snrnps, before returning to the nucleus. among the u6 snrnps, loss of lsm6 or lsm7 induces a cytosolic accumulation of u6 snrna. recently, u6 has been shown to be ma - modified by mettl16 at a43. in schizosaccharomyces pombe, loss of the mettl16 ortholog mtl16 alters global splicing. in contrast, in mouse embryos, mettl16 deletion had little effect on global splicing. these contrasting functions suggest species - specific roles for mettl16 in splicing. altogether, the functional role of ma methylation on u6 snrna in mammals as well as its reader remains unknown. emerging evidence has demonstrated that inflammation, originally recognized for its pivotal role in pathogen defense, also plays critical roles in a number of diseases including cancer and autoimmune diseases, both of which can be induced or triggered by environmental factors such as uv radiation. however, the molecular mechanisms that regulate inflammation remain incompletely understood. here we show that ythdf2 recognizes ma - modified u6 snrna to regulate u6 stability and binds to tlr3 in the context of inflammation and tumorigenesis, highlighting the crucial role of ythdf2 and u6 ma methylation in controlling inflammation. recently, we have shown that the ma reader ythdf1 regulates the repair of genome damage caused by uvb stress. however, the role of other ma readers, including ythdf2, in stress responses remains poorly understood. to determine the functional role of ythdf2, we performed rna - seq in hacat cells, non-tumorigenic human keratinocytes, to identify pathways affected by ythdf2 loss. our analysis showed that ythdf2 knockdown upregulates genes in several pathways, including the tnf and il - 17 signaling pathway, signaling by interleukins, tlr3 cascade, and antiviral pathways ( fig. 1a, supplementary fig. s1a ), suggesting that ythdf2 may act as a regulator of inflammation. next, to determine whether ythdf2 has a role in the uvb stress response, we performed mass spectrometric analysis to identify pathways associated with ythdf2 - interacting proteins in hacat cells ( supplementary table s1 ). we compared these pathways with pathways of genes upregulated by uvb irradiation from our previous work in hacat cells ( gse145924 ). analyzing both data sets, we found that genes up - regulated by uvb share several pathways with ythdf2 - interacting proteins, including metabolism of rna and ribonucleoprotein complex biogenesis ( fig. 1b, supplementary fig. s1b ), suggesting that ythdf2 may play an important role in the uvb - induced stress response. fig. 1ythdf2 controls inflammatory gene expression. a pathway enrichment of genes upregulated upon ythdf2 knockdown in hacat cells ( rna - seq, q < 0. 05, deseq2 ). b overlap between the top 20 uvb - induced pathways ( rna - seq ) and the top 10 pathways of ythdf2 - interacting proteins ( mass spectrometry, 1 h post - sham or - uvb ). c representative h & e staining of skin sections 24 h after sham or uvb exposure in wt ( ythdf2 ) and df2 cko ( k14cre; ythdf2 ) mice. n = 3 mice per group. d quantification of epidermal thickness ( n = 3 ). e cd45 cell counts in skin of sham - and uvb - irradiated wt and df2 cko mice ( n = 5 ). f box plots of ythdf2 expression across systemic lupus erythematosus ( sle ) datasets. centre line, median; box, interquartile range; whiskers, minimum to maximum.