Abstracts (complete list) - Wissenschaft Online

Julia Kzhyshkowska, Alexei Gratchev, Liis Krusell, Srinivas Mamidi, Gail Workman, E.
Helene Sage, Sergij Goerdt
Scavenger receptor stabilin-1 links endocytosis and
intracellular sorting in alternatively activated macrophages
The multifunctional scavenger receptor stabilin-1 is expressed on macrophages on
placenta and adult tissues as well as on sinusoidal endothelial cells and macrophages in
lymph nodes. In vitro induction of stabilin-1 on macrophages requires IL-4 and
glucocorticoids. We showed that stabilin-1 mediates endocytosis of extracellular ligands
acLDL, regulator of ECM-remodelling and cell adhesion SPARC, and hormone placental
lactogen (PL). Both SPARC and acLDL are targeted via stabilin-1 for the degradation in
lysosomes. In contrast, a portion of PL escapes degradation and is delivered into novel
storage vesicles. These vesicles do not belong to classical endosomal/lysosomal system.
However these vesicles communicate with trans-Golgi network (TGN). Stored PL can be
secreted back to the extracellular space. Next, we found that stabilin-1 shuttles
between TGN and endosomes. This trafficking pathway is mediated by GGAs, clathrin
adaptors that interact with the DDSLL motif in the cytoplasmic tail of stabilin-1. Here
stabilin-1 is involved in delivery of the novel chitinase-like protein SI-CLP from TGN to
the endosomal/lysosomal compartment.
SI-CLP was identified by us as a binding partner for stabilin-1 in yeast two-hybrid
screening. SI-CLP contains a conservative lectin-type Glyco_18 domain, which lacks
enzymatic activity, similarly to YKL-40 and Ym1/Ym2. YKL-40 and Ym1/Ym2 are
secreted by macrophages, possess cytokine activity and are associated with Th2-type
inflammations and allergies. We demonstrated that endogenous SI-CLP is
overexpressed in human macrophages stimulated with IL-4 and dexamethasone and is
transported via stabilin-1 from biosynthetic to the secretory pathway. High levels of SI-
CLP were detected in bronchoalveolar lavage samples from patients with chronic
bronchitis.
We propose that alternatively-activated macrophages use stabilin-1 1) to coordinate
ECM remodeling, angiogenesis, and tissue turnover via endocytosis and degradation of
SPARC; 2) to regulate extracellular concentration of PL in placenta; 3) to regulate
delivery of chitinase-like protein SI-CLP into the secretory pathway.