Late endosomes promote microglia migration via cytosolic translocation of immature protease cathD

Yi-Jun Liu1, Ting Zhang2, Daxiao Cheng2

  • 1Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China. duanshumin@zju.edu.cn xiaodongwang@zju.edu.cn margareth@shanghaitech.edu.cn yjliu@zju.edu.cn.

Science Advances
|December 10, 2020
PubMed

Insights

Late endosomes regulate actin cytoskeleton remodeling through the translocation of immature cathepsin D (cathD) during microglia migration. This process is crucial for maintaining cell movement and actin dynamics.

Area of Science:

  • Cell Biology
  • Cytoskeleton Dynamics
  • Organelle Biology

Background:

  • Organelle transport relies on cytoskeleton remodeling.
  • The reciprocal regulation of cytoskeletal dynamics by organelles is not well understood.

Purpose of the Study:

  • To investigate the role of late endosomes in regulating actin cytoskeleton dynamics.
  • To identify specific molecules involved in organelle-mediated cytoskeletal remodeling during microglia migration.

Main Methods:

  • Studied microglia migration using live-cell imaging.
  • Investigated the role of cathepsin D (cathD) and its translocation.
  • Analyzed the impact of cathD manipulation on actin dynamics and cofilin activity.

Main Results:

  • Late endosomes facilitate actin remodeling via cytosolic translocation of immature cathD.
  • Translocated cathD localizes to the leading edge of lamellipodia.
  • Suppression of cathD impairs lamellipodial maintenance and balances cofilin activity, maintaining the globular-actin (G-actin) pool.

Conclusions:

  • Immature cathD, translocated from late endosomes, is a key regulator of actin cytoskeleton remodeling.
  • This unconventional role of cathD is essential for sustained microglia migration.

Related Concept Videos

Maturation of Endosomes01:28

Maturation of Endosomes

The early endosome containing internalized molecules matures through transformations in its location, morphology, intraluminal pH, and membrane protein composition. Together, these changes result in a more acidic late endosome that contains multiple intraluminal vesicles; therefore, the late endosome is also called a multivesicular body (MVB).
Changes in location
The maturing endosome moves along microtubules from the periphery of the cell towards the perinuclear region. This movement of the...
5.2K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
4.7K
Intralumenal Vesicles and Multivesicular Bodies01:38

Intralumenal Vesicles and Multivesicular Bodies

Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the...
4.4K
The Early Endosome: Endocytosis of Transferrin01:28

The Early Endosome: Endocytosis of Transferrin

Essential proteins such as insulin or low-density lipoprotein (LDL) and micronutrients such as iron enter a eukaryotic cell through receptor-mediated endocytosis. Subsequently, the early endosomes fuse with the vesicles containing such receptor-ligand complexes and play a vital role in sorting the incoming ligands and receptors. While the ligands are either degraded inside the vesicle or released into the cytosol, their receptors are returned to the plasma membrane for further rounds of...
4.4K
Clathrin Coated Vesicles01:12

Clathrin Coated Vesicles

Clathrin-coated vesicles use endocytosis to transport receptors and lysosomal hydrolases from the Golgi to the lysosome in the late secretory pathway. Clathrin-mediated endocytosis was the first described endocytic process, and Clathrin-coated vesicles remain one of the most well-studied transport vesicles. The molecular machinery that generates clathrin-coated vesicles comprises over 50 proteins that precisely coordinate vesicle formation. Cell surface receptors concentrated in indented sites...
8.5K
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
10.4K