KDEL receptor cycles between the ER and the Golgi to retrieve ER-resident chaperones that get leaked to the secretory pathway during protein export from the ER. Recent studies have shown that a fraction of KDEL receptor may reside in the plasma membrane and function as a putative cell surface receptor. However, the trafficking itinerary and mechanism of cell surface expressed KDEL receptor remains largely unknown. In this study, we used N-terminally Halo-tagged KDEL receptor to investigate its endocytosis from the plasma membrane and trafficking itinerary of the endocytosed receptor through the endolysosomal compartments. Our results indicate that surface-expressed KDEL receptor undergoes highly complex recycling pathways via the Golgi and peri-nuclear recycling endosomes that are positive for Rab11 and Rab14, respectively. Unexpectedly, KDEL receptor appears to preferentially utilize clathrin-mediated endocytic pathway as well as clathrin-dependent transport carriers for export from the trans-Golgi network. Taken together, we suggest that KDEL receptor may be a bona fide cell surface receptor with a complex, yet well-defined trafficking itinerary through the endolysosomal compartments.

KDEL受体在内质网和高尔基体之间循环，以检索内质网驻留的伴侣蛋白，这些伴侣蛋白在从内质网蛋白输出时泄漏到分泌途径中。最近的研究表明，一部分KDEL受体可能驻留在质膜中，并作为假定的细胞表面受体起作用。但是，细胞表面表达的KDEL受体的运输路线和机制仍然未知。在这项研究中，我们使用N末端带有Halo标签的KDEL受体来研究其从质膜的内吞作用，以及通过内溶酶体区室运输内吞受体的行程。我们的结果表明，表面表达的KDEL受体通过高尔基体和核周再循环内体经历高度复杂的再循环途径，这些内体分别对Rab11和Rab14呈阳性。不料，反-高尔基网络。两者合计，我们建议KDEL受体可能是真正的细胞表面受体，具有通过溶酶体区室的复杂但定义明确的运输路线。