Work

A dileucine motif in TMEM163 is essential for its binding with both AP-3 and BLOC-1 complex

Year: 2026

Type: article

Abstract: Defects in Hermansky-Pudlak syndrome protein associated complexes impair the biogenesis of lysosome-related organelles ( e.g. platelet dense granule). Transmembrane protein 163 (TMEM163), a zinc transporter, is drastically reduced in platelets of AP-3-, BLOC-1-, and BLOC-2-deficient Hermansky-Pudlak syndrome mice and patients, but the mechanistic basis is unclear. We here found that TMEM163 was reduced and degraded primarily via the proteasome in a variety of deficient MEG-01 cells of endosomal trafficking complexes (AP-1, AP-2, AP-3, BLOC-1, BLOC-2). A conserved N-terminal acidic dileucine motif (LEDRGL 69 L 70 ) in TMEM163 is essential for interactions with BLOC-1 and AP-3 but dispensable for binding with AP-1, AP-2 and BLOC-2. Mutation of this motif led to TMEM163 accumulation in the plasma membrane. Loss of either BLOC-1 or AP-3 enhanced TMEM163 bound to the other and exhibited differential abnormal endo-lysosomal localization, suggesting competitive binding during TMEM163 trafficking. Collectively, our findings established TMEM163 as a cargo protein sequentially sorted by AP-3 and BLOC-1 via a shared dileucine-based sorting signal, which is essential for its proper trafficking to platelet dense granules, uncovering a unique mechanism in Hermansky-Pudlak syndrome protein associated complex cargo sorting and lysosome-related organelle biogenesis.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.111451

Authors: Zhuang Qi, Yefeng Yuan, Wei Li

Institutions: Capital Medical University, Beijing Children’s Hospital

Language: English

Topic: Cellular transport and secretion

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $3,430

Funders: National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China