[JCS RESEARCH HIGHLIGHT]
Derlins and Surf4 work together to ERADicate COX-2
Cyclooxygenase-2 (COX-2) is a crucial enzyme in the synthesis of eicosanoids, signalling molecules that regulate a broad array of physiological processes. COX-2 is dynamically regulated in response to many hormones, growth factors and cytokines, which can require accelerated degradation of COX-2 via ER-associated degradation (ERAD). ERAD involves retrotranslocation of ER-resident proteins and extraction by the ATPase p97 prior to proteasomal degradation. Although diverse factors involved in retrotranslocation and ERAD have been described, degradation of many ER-resident proteins requires specific combinations of factors that have not been defined. This study investigates the ERAD machinery involved in COX-2 degradation and identify the ER membrane proteins derlin-1, derlin-2 and Surf4 as facilitators of COX-2 degradation upstream of p97. By carefully assessing protein–protein interactions, the authors resolve the sequential requirement of derlin-2, derlin-1, Surf4, caveolin-1 and p97 for efficient COX-2 degradation. Whereas degradation of COX-2 is dependent on its N-glycosylation state, its interaction with this ERAD machinery occurs regardless of glycosylation. Surf4, which typically regulates ER protein secretion, represents an unexpected player in this ERAD machinery. Taken together, these findings uncover a unique degradation pathway for COX-2 that might contribute to its dynamic and rapid regulation.

Cyclooxygenase-2 (COX-2) 是合成前列腺素等信號分子的關鍵酶，調控多種生理過程。COX-2受多種激素、生長因數和細胞因數的動態調控，這可能需要通過內質網相關降解（ERAD）來加速降解COX-2。透過p97的協助，ERAD進行內質網內蛋白反向轉運（retrotranslocation）至細胞質，然後進行蛋白酶體降解。儘管有許多研究涉及反向轉運和ERAD的調控因素，但許多內質網內蛋白的降解需要特定的因素組合，這些組合尚未定義。本研究調查了參與COX-2降解的ERAD機制，並確定了ER膜蛋白derlin-1、derlin-2 和 Surf4 作為促進 COX-2 降解的因數。通過仔細評估蛋白質間的相互作用，作者揭示了derlin-2、derlin-1、Surf4、caveolin-1 和 p97 的蛋白序列為高效調控COX-2降解的機轉。雖然COX-2的降解依賴於其N-糖基化狀態，但這種ERAD機制的相互作用不受糖基化的影響。Surf4通常會調控ER蛋白的分泌，成為ERAD的一員，是一個意想不到的參與者。綜上所述，這些發現揭示了COX-2的獨特降解途徑，可能有助於其動態和迅速的調控。