Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
Mol Cell Biol. 2018 Jun 14;38(13). doi: 10.1128/MCB.00154-18. Print 2018 Jul 1.
A balance between protein synthesis and degradation is necessary to maintain cellular homeostasis. Failure to triage aberrant proteins may result in their accumulation and aggregation in the cytosol. The valosin-containing protein (VCP)-BCL2-associated athanogene 6 (BAG6) complex facilitates a wide variety of ubiquitin-mediated quality control events at the endoplasmic reticulum (ER), both prior to ER translocation and during ER-associated degradation (ERAD). However, how ubiquitylated clients associated with BAG6 are recognized by VCP for proteasomal degradation is presently unknown. We have identified UBXN1 as the VCP adaptor in BAG6-dependent processes occurring prior to ER insertion but not during ERAD. The loss of VCP-UBXN1 results in the inappropriate stabilization of ubiquitylated BAG6 clients and their accumulation in insoluble aggregates and sensitizes cells to proteotoxic stress. Our results identify how VCP is specifically targeted to ubiquitylated substrates in the BAG6 triage pathway and suggest that the degradation of ubiquitylated clients by the proteasome is reliant on the association of UBXN1 with ubiquitylated substrates and the catalytic activity of VCP.
蛋白质的合成与降解之间需要达到平衡，才能维持细胞内环境稳定。如果不能对异常蛋白质进行分类处理，可能会导致它们在细胞质中积累和聚集。含缬氨酸蛋白（VCP）-BCL2 相关抗凋亡基因 6（BAG6）复合物有助于在多种泛素介导的质量控制事件中发挥作用，包括内质网（ER）易位之前和 ER 相关降解（ERAD）期间。然而，目前尚不清楚与 BAG6 相关的泛素化客户如何被 VCP 识别，以便进行蛋白酶体降解。我们已经确定 UBXN1 是 BAG6 依赖性过程中 VCP 的接头，该过程发生在 ER 插入之前，但不在 ERAD 期间。VCP-UBXN1 的缺失会导致泛素化 BAG6 客户的不适当稳定，并导致其在不可溶性聚集体中积累，从而使细胞对蛋白毒性应激敏感。我们的研究结果确定了 VCP 如何在 BAG6 分类途径中特异性靶向泛素化底物，并表明蛋白酶体对泛素化底物的降解依赖于 UBXN1 与泛素化底物的结合以及 VCP 的催化活性。
