Glycoprotein-induced phase separation drives unconventional secretion of galectin-3
- Zihan Zhao
- Zhen He
- Hongming Gu
- Andong Zhou
- Yibing Wang
- Zhaoyi Liang
- Jie Geng
- Xuejiao Xu
- Menghui Wang
- Chunyao Li
- Yuying Fan
- Hairong Cheng
- Lin Sun
- Kevin H. Mayo
- Avraham Raz
- Guihua Tai
- Yifa Zhou
2026-08-06
The mechanism of unconventional protein secretion remains an unresolved issue. Here, we describe an unconventional protein secretion pathway for galectin-3 that is mediated by phase separation and condensation. Using four lysosomal damage models, we observed a rapid, pronounced release of galectin-3 in large, non-exosomal particles. This secretion is driven by glycoprotein-induced galectin-3 phase separation and is independent of pyroptosis and secretory autophagy. During phase separation, the S-face of galectin-3 carbohydrate recognition domain binds glycoproteins that triggers galectin-3 N-terminal tail release and condensation. These condensates then recruit ALG-2 via the exposed N-terminal tail. ALG-2 directs the condensates to the endoplasmic reticulum–late endosome interface. After translocation into late endosomes, galectin-3 condensates are secreted into the extracellular milieu by SNARE-dependent vesicular transport. This mechanism of exporting phase-separated protein condensates may serve as a clean-up response to membrane damage.