Non-canonical isoforms of the mRNA polyadenylation factor WDR33 regulate STING-mediated immune responses

Area of Science:

• Molecular Biology
• Immunology
• Cell Biology

Background:

• The WDR33 gene encodes three major isoforms: WDR33v1, WDR33v2, and WDR33v3.
• WDR33v1 is a known nuclear mRNA polyadenylation factor.
• The functions of WDR33v2 and WDR33v3 were previously uncharacterized.

Purpose of the Study:

• To investigate the functions of WDR33v2 and WDR33v3.
• To explore the role of these isoforms in cellular processes and immune responses.
• To understand the regulatory mechanisms of the stimulator of interferon genes (STING) pathway.

Main Methods:

• Analysis of alternative polyadenylation in WDR33 gene expression.
• Protein localization studies using endoplasmic reticulum markers.
• Co-immunoprecipitation assays to identify protein interactions with STING.
• Assessment of interferon-β induction and autophagy markers.
• Investigation of STING protein levels and oligomerization.

Main Results:

• WDR33v2 and WDR33v3 are generated by alternative polyadenylation and lack full WD repeats.
• These isoforms localize to the endoplasmic reticulum and interact with STING.
• WDR33v2 suppresses interferon-β induction by inhibiting STING oligomerization and promotes autophagy.
• WDR33v3 enhances STING protein levels.
• The study reveals functionally distinct roles for WDR33 isoforms.

Conclusions:

• Alternative polyadenylation generates functionally divergent WDR33 protein isoforms.
• WDR33v2 and WDR33v3 play critical roles in regulating the innate immune response via STING.
• These findings highlight the significant impact of alternative mRNA processing on protein function and cellular regulation.