Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Allianz, Heidelberg, Germany.
Lehrstuhl für Chemie der Biopolymere, Department für Biowissenschaftliche Grundlagen, Technische Universität München, Freising, Germany.
EMBO J. 2014 Nov 3;33(21):2492-506. doi: 10.15252/embj.201488208. Epub 2014 Sep 19.
Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of signal peptides at the endoplasmic reticulum (ER), but has also been suggested to play a role in ER-associated degradation (ERAD). Here, we show that SPP forms a complex with the ERAD factor Derlin1 and the E3 ubiquitin ligase TRC8 to cleave the unfolded protein response (UPR) regulator XBP1u. Cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an SPP substrate through specific sequence features. Additionally, Derlin1 acts in the complex as a substrate receptor by recognizing the luminal tail of XBP1u. Remarkably, this interaction of Derlin1 with XBP1u obviates the need for ectodomain shedding prior to SPP cleavage, commonly required for intramembrane cuts. Furthermore, we show that XBP1u inhibits the UPR transcription factor XBP1s by targeting it toward proteasomal degradation. Thus, we identify an ERAD complex that controls the abundance of XBP1u and thereby tunes signaling through the UPR.
信号肽肽酶（SPP）在 ER 中催化信号肽的膜内水解，但也被认为在 ER 相关降解（ERAD）中发挥作用。在这里，我们表明 SPP 与 ERAD 因子 Derlin1 和 E3 泛素连接酶 TRC8 形成复合物，以切割未折叠蛋白反应（UPR）调节剂 XBP1u。切割发生在一个迄今为止尚未被识别的 II 型跨膜结构域内，该结构域通过特定的序列特征使 XBP1u 成为 SPP 的底物。此外，Derlin1 通过识别 XBP1u 的腔尾作为底物受体在复合物中发挥作用。值得注意的是，Derlin1 与 XBP1u 的这种相互作用消除了 SPP 切割前通常需要的外结构域脱落，这是膜内切割所必需的。此外，我们表明 XBP1u 通过将其靶向蛋白酶体降解来抑制 UPR 转录因子 XBP1s。因此，我们确定了一个 ERAD 复合物，该复合物控制 XBP1u 的丰度，从而调节通过 UPR 的信号转导。
