Progranulin (PGRN) is a glycoprotein implicated in several neurodegenerative diseases. It is highly expressed in microglia and macrophages and can be secreted or delivered to the lysosome compartment. PGRN comprises 7.5 granulin repeats and is processed into individual granulin peptides within the lysosome, but the functions of these peptides are largely unknown. Here, we identify CD68, a lysosome membrane protein mainly expressed in hematopoietic cells, as a binding partner of PGRN and PGRN-derived granulin E. Deletion analysis of CD68 showed that this interaction is mediated by the mucin–proline-rich domain of CD68. While CD68 deficiency does not affect the lysosomal localization of PGRN, it results in a specific decrease in the levels of granulin E but no other granulin peptides. On the other hand, the deficiency of PGRN, and its derivative granulin peptides, leads to a significant shift in the molecular weight of CD68, without altering CD68 localization within the cell. Our results support that granulin E and CD68 reciprocally regulate each other’s protein homeostasis.

颗粒蛋白前体 (PGRN) 是一种与几种神经退行性疾病有关的糖蛋白。它在小胶质细胞和巨噬细胞中高度表达，可以分泌或递送到溶酶体隔室。PGRN 包含 7.5 个颗粒蛋白重复序列​​，并在溶酶体内加工成单个颗粒蛋白肽，但这些肽的功能在很大程度上是未知的。在这里，我们将 CD68（一种主要在造血细胞中表达的溶酶体膜蛋白）鉴定为 PGRN 和 PGRN 衍生的颗粒蛋白 E 的结合伙伴。CD68 的缺失分析表明这种相互作用是由 CD68 的富含粘蛋白 - 脯氨酸的结构域介导的。虽然 CD68 缺乏不会影响 PGRN 的溶酶体定位，但它会导致颗粒蛋白 E 水平的特异性降低，但不会导致其他颗粒蛋白肽的水平下降。另一方面，PGRN的不足，及其衍生的颗粒蛋白肽，导致 CD68 的分子量发生显着变化，而不会改变 CD68 在细胞内的定位。我们的结果支持颗粒蛋白 E 和 CD68 相互调节彼此的蛋白质稳态。