Kimpler Lisa A, Glosson Nicole L, Downs Deanna, Gonyo Patrick, May Nathan A, Hudson Amy W
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
PLoS One. 2014 Jun 5;9(6):e99139. doi: 10.1371/journal.pone.0099139. eCollection 2014.
The human herpesvirus-7 (HHV-7) U21 gene product binds to class I major histocompatibility complex (MHC) molecules and reroutes them to a lysosomal compartment. Trafficking of integral membrane proteins to lysosomes is mediated through cytoplasmic sorting signals that recruit heterotetrameric clathrin adaptor protein (AP) complexes, which in turn mediate protein sorting in post-Golgi vesicular transport. Since U21 can mediate rerouting of class I molecules to lysosomes even when lacking its cytoplasmic tail, we hypothesize the existence of a cellular protein that contains the lysosomal sorting information required to escort class I molecules to the lysosomal compartment. If such a protein exists, we expect that it might recruit clathrin adaptor protein complexes as a means of lysosomal sorting. Here we describe experiments demonstrating that the μ adaptins from AP-1 and AP-3 are involved in U21-mediated trafficking of class I molecules to lysosomes. These experiments support the idea that a cellular protein(s) is necessary for U21-mediated lysosomal sorting of class I molecules. We also examine the impact of transient versus chronic knockdown of these adaptor protein complexes, and show that the few remaining μ subunits in the cells are eventually able to reroute class I molecules to lysosomes.
人类疱疹病毒7型（HHV-7）的U21基因产物可与I类主要组织相容性复合体（MHC）分子结合，并将其重新导向溶酶体区室。完整膜蛋白向溶酶体的运输是通过细胞质分选信号介导的，这些信号招募异源四聚体网格蛋白衔接蛋白（AP）复合体，进而在高尔基体后囊泡运输中介导蛋白质分选。由于即使U21缺乏其细胞质尾巴也能介导I类分子向溶酶体的重新导向，我们推测存在一种细胞蛋白，它包含将I类分子护送至溶酶体区室所需的溶酶体分选信息。如果存在这样一种蛋白，我们预计它可能会招募网格蛋白衔接蛋白复合体作为溶酶体分选的一种方式。在此，我们描述了一些实验，证明来自AP-1和AP-3的μ衔接蛋白参与了U21介导的I类分子向溶酶体的运输。这些实验支持了这样一种观点，即一种细胞蛋白对于U21介导的I类分子溶酶体分选是必需的。我们还研究了这些衔接蛋白复合体瞬时与长期敲低的影响，并表明细胞中剩余的少数μ亚基最终能够将I类分子重新导向溶酶体。
