Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
Cells. 2023 Nov 30;12(23):2741. doi: 10.3390/cells12232741.
The ubiquitin E3 ligase UBE3C promotes the proteasomal degradation of cytosolic proteins and endoplasmic reticulum (ER) membrane proteins. UBE3C is proposed to function downstream of the RNF185/MBRL ER-associated degradation (ERAD) branch, contributing to the ERAD of select membrane proteins. Here, we report that UBE3C facilitates the ERAD of misfolded CFTR, even in the absence of both RNF185 and its functional ortholog RNF5 (RNF5/185). Unlike RNF5/185, UBE3C had a limited impact on the ubiquitination of misfolded CFTR. UBE3C knockdown (KD) resulted in an additional increase in the functional ∆F508-CFTR channels on the plasma membrane when combined with the RNF5/185 ablation, particularly in the presence of clinically used CFTR modulators. Interestingly, although UBE3C KD failed to attenuate the ERAD of insig-1, it reduced the ERAD of misfolded ∆Y490-ABCB1 and increased cell surface expression. UBE3C KD also stabilized the mature form of ∆F508-CFTR and increased the cell surface level of T70-CFTR, a class VI CFTR mutant. These results suggest that UBE3C plays a vital role in the ERAD of misfolded CFTR and ABCB1, even within the RNF5/185-independent ERAD pathway, and it may also be involved in maintaining the peripheral quality control of CFTR.
泛素 E3 连接酶 UBE3C 促进细胞质蛋白和内质网 (ER) 膜蛋白的蛋白酶体降解。UBE3C 被认为在下游的 RNF185/MBRL ER 相关降解 (ERAD) 分支中发挥作用，有助于选择膜蛋白的 ERAD。在这里，我们报告 UBE3C 促进错误折叠 CFTR 的 ERAD，即使在缺乏 RNF185 和其功能同源物 RNF5（RNF5/185）的情况下也是如此。与 RNF5/185 不同，UBE3C 对错误折叠 CFTR 的泛素化作用影响有限。UBE3C 敲低 (KD) 与 RNF5/185 消融结合时，会导致质膜上功能性 ∆F508-CFTR 通道的额外增加，特别是在存在临床使用的 CFTR 调节剂的情况下。有趣的是，尽管 UBE3C KD 未能减弱 insig-1 的 ERAD，但它减少了错误折叠 ∆Y490-ABCB1 的 ERAD，并增加了细胞表面表达。UBE3C KD 还稳定了 ∆F508-CFTR 的成熟形式，并增加了 T70-CFTR 的细胞表面水平，T70-CFTR 是一种 VI 类 CFTR 突变体。这些结果表明，UBE3C 在内质网独立的 RNF5/185 途径中，甚至在错误折叠 CFTR 和 ABCB1 的 ERAD 中发挥重要作用，它也可能参与维持 CFTR 的外周质量控制。
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