Identification of RNA uridylation subtypes, and the prognostic and therapeutic value of RNA uridylation in systemic lupus erythematosus.

The uridylation of 3'-RNA-a major process in epitranscriptomics- is catalyzed by terminal uridylyl transferases (TUTases), which are involved in multiple diseases and the immune response. Nonetheless, the role of TUTases in systemic lupus erythematosus (SLE) remains unknown. Here we identified increased level of MTPAP and ZCCHC6 and decreased level of PAPD5 and ZCCHC11 in SLE patients from Gene Expression Omnibus (GEO) GSE50772, GSE65391, and GSE121239. The random forest model was applied to screen 4 TUTase candidates (MTPAP, ZCCHC6, PAPD5, and ZCCHC11) to predict the susceptibility of SLE. A nomogram was constructed based on the 4 selected TUTase regulators. Decision curve analysis indicated that patients could benefit from the nomogram. Moreover, based on the 4 differentially expressed genes, individuals with SLE were divided into three patterns (Cluster A-C) using the consensus clustering method. Cluster B was enriched in adaptive immune cells, with the lowest TCE signature expression, manifesting a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) than that in Cluster A and C. whereas, Cluster C was enriched in innate immune cells, with the highest T-cell exhaustion (TCE) signature expression, manifesting lower SLEDAI than that in Cluster B. Clinically, lupus nephritis (LN) patients manifested increased expression of MTPAP and ZCCHC6 and decreased expression of PAPD5 and ZCCHC11 in PBMCs using Quantitative Polymerase Chain Reaction (q-PCR). Immunohistochemistry (IHC) illustrated higher level of ZCCHC6 in the kidneys of LN patients than that in NC. In summary, TUTases could predict the occurrence of SLE and stratify patients based on their immune characteristics, eventually predicting the disease activity and guiding immune therapy.