Wdr33 is a gene encoding a central component of the mRNA polyadenylation (PA) machinery in humans. It plays a crucial role in the 3'-end processing of polyadenylated mRNAs, with its encoded protein being involved in recognizing the polyadenylation signal AAUAAA, which is vital for pre-mRNA cleavage and polyadenylation [3,4,5,6,7]. This process is essential for mRNA maturation and thus impacts various biological processes.

The human Wdr33 gene generates three major isoforms. The canonical isoform WDR33v1 is a well-characterized nuclear mRNA polyadenylation factor. In contrast, WDR33v2 and WDR33v3, produced by alternative polyadenylation, lack all seven WD repeats of V1. Surprisingly, V2 and V3 are not polyadenylation factors but localize to the endoplasmic reticulum, interact with stimulator of interferon genes (STING), and regulate STING-mediated immune responses. V2 suppresses interferon-β induction and promotes autophagy, while V3 increases STING protein levels [2]. Also, the levels of the PA factor CFIm25 modulate V2 and V3 expression, and their PA site usage varies in distinct immune responses. The usage of WDR33 alternative PA sites is stochastic, depending on a complex interplay between splicing and PA [1].

In conclusion, Wdr33 is essential for mRNA polyadenylation and has a significant impact on immune-related biological functions through its non-canonical isoforms. Studies on Wdr33 contribute to our understanding of mRNA processing mechanisms and immune-response regulation, potentially providing insights into related disease areas such as immune-disorder-associated pathologies.

References:

1. Liu, Lizhi, Seimiya, Takahiro, Manley, James L. 2024. WDR33 alternative polyadenylation is dependent on stochastic poly(a) site usage and splicing efficiencies. In RNA biology, 21, 25-35. doi:10.1080/15476286.2024.2408708. https://pubmed.ncbi.nlm.nih.gov/39327832/

2. Liu, Lizhi, Manley, James L. 2024. Non-canonical isoforms of the mRNA polyadenylation factor WDR33 regulate STING-mediated immune responses. In Cell reports, 43, 113886. doi:10.1016/j.celrep.2024.113886. https://pubmed.ncbi.nlm.nih.gov/38430516/

3. Chan, Serena L, Huppertz, Ina, Yao, Chengguo, Manley, James L, Shi, Yongsheng. 2014. CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3' processing. In Genes & development, 28, 2370-80. doi:10.1101/gad.250993.114. https://pubmed.ncbi.nlm.nih.gov/25301780/

4. Schönemann, Lars, Kühn, Uwe, Martin, Georges, Zavolan, Mihaela, Wahle, Elmar. 2014. Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33. In Genes & development, 28, 2381-93. doi:10.1101/gad.250985.114. https://pubmed.ncbi.nlm.nih.gov/25301781/

5. Sun, Yadong, Zhang, Yixiao, Hamilton, Keith, Walz, Thomas, Tong, Liang. 2017. Molecular basis for the recognition of the human AAUAAA polyadenylation signal. In Proceedings of the National Academy of Sciences of the United States of America, 115, E1419-E1428. doi:10.1073/pnas.1718723115. https://pubmed.ncbi.nlm.nih.gov/29208711/

6. Hamilton, Keith, Sun, Yadong, Tong, Liang. 2019. Biophysical characterizations of the recognition of the AAUAAA polyadenylation signal. In RNA (New York, N.Y.), 25, 1673-1680. doi:10.1261/rna.070870.119. https://pubmed.ncbi.nlm.nih.gov/31462423/

7. Gutierrez, Pedro A, Wei, Jia, Sun, Yadong, Tong, Liang. 2022. Molecular basis for the recognition of the AUUAAA polyadenylation signal by mPSF. In RNA (New York, N.Y.), 28, 1534-1541. doi:10.1261/rna.079322.122. https://pubmed.ncbi.nlm.nih.gov/36130077/