TMEM203 is a conserved transmembrane protein with dual roles in calcium homeostasis and innate immune signaling. Primarily, TMEM203 regulates intracellular calcium by modulating endoplasmic reticulum (ER) calcium stores; its overexpression reduces ER calcium while elevating basal cytoplasmic levels 1. The protein localizes to the ER where it associates with calcium regulatory proteins 1. TMEM203 is essential for male fertility, as knockout mice exhibit severe spermiogenesis defects due to altered calcium handling in spermatocytes 1. Beyond reproduction, TMEM203 acts as a critical regulator of STING-mediated innate immunity. It directly interacts with STING and promotes TBK1 kinase activation and IRF3 transcription factor signaling, leading to type I interferon expression in macrophages 2. This regulatory role has disease implications: TMEM203 expression is elevated in systemic lupus erythematosus (SLE) patients and correlates with disease activity 2, suggesting dysregulation contributes to excessive type I interferon production characteristic of this autoimmune condition. Additionally, TMEM203 suppresses hepatitis B virus replication through its calcium-regulatory function 3, indicating its importance in antiviral defense.