TMEM129 is a tri-spanning ER-resident E3 ubiquitin ligase essential for ER-associated protein degradation (ERAD) 1. It functions as a novel unconventional C4C4-type RING finger E3 ubiquitin ligase that preferentially associates with the E2 enzyme UBE2J2 to catalyze ubiquitination of misfolded ER proteins destined for cytosolic proteasomal degradation 23. TMEM129 is positioned within an ER-resident dislocation complex containing Derlin-1, Derlin-2, VIMP, and p97, positioning its C-terminal RING domain in the cytosol to facilitate ubiquitination reactions 1. Pathologically, TMEM129 is exploited by human cytomegalovirus US11 protein to mediate HLA class I and FcRn receptor degradation, enabling viral immune evasion 24. Beyond viral manipulation, TMEM129 expression is genetically modulated in osteoarthritis through methylation at rs11732213, with the disease risk allele showing reduced expression, implicating TMEM129 as a susceptibility target in ER proteostasis-related pathology 5. Additionally, TMEM129 demonstrates prognostic value in cancer, emerging as a biomarker for breast cancer survival prediction and ovarian cancer recurrence risk stratification 67. These findings establish TMEM129 as a critical regulator of proteostasis with roles spanning viral pathogenesis, degenerative disease, and malignancy.