Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, United States.
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, United States.
Elife. 2024 Nov 12;12:RP89606. doi: 10.7554/eLife.89606.
Degrons are minimal protein features that are sufficient to target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, all of the identified degrons only function within the cytosol. Using , we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate proteasomal degradation through the endoplasmic reticulum associated degradation (ERAD) system. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation in budding yeast and mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and builds toward therapeutic approaches that exploit the highly conserved ERAD system.
肽段是能够将蛋白质靶向降解的最小蛋白特征。在大多数情况下，肽段允许被细胞质泛素蛋白酶体系统的成分识别。目前，所有已鉴定的肽段仅在细胞质中起作用。我们使用这项技术，从内质网（ER）腔中鉴定出了第一个作为 ER 腔中功能的短线性序列。我们表明，当这些肽段被转移到蛋白质上时，它们通过内质网相关降解（ERAD）系统促进蛋白酶体降解。这些肽段能够降解腔和完整膜 ER 蛋白，从而扩大了可以在出芽酵母和哺乳动物组织培养中靶向降解的蛋白质类型。这一发现为从以前无法到达的内质网腔靶向蛋白质降解提供了一个框架，并为利用高度保守的 ERAD 系统的治疗方法奠定了基础。
