Phagocyte Biology Laboratory

Dr. Bryan Heit, Western University

Model of Rab17 Function

Model of Rab17 Activity (click for full-size). Legend: EE – early endosome, LE – late endosome, LY – lysosome, RE – recycling endosome

We are excited to announce the publication of a follow-up paper to last-years study of Rab17 mediate sorting of antigens. In our first study we identified Rab17 as a protein which allowed macrophages to prevent generating immune responses after engulfing dead cells (a process termed efferocytosis), while still allowing macrophages to generate immune responses after engulfing pathogens. In this new study we have further explored this Rab17-dependent sorting pathway, revealing the details of how this process works.

Background:

To understand what Rab17 is doing we first need to talk – briefly – about how macrophages process pathogens. Macrophages “eat” pathogens, with engulfed pathogens ending up in a “stomach” called the “phagosome”.The phagosome then moves towards the centre of the macrophage, where it can fuse with lysosomes. This fusion delivers  enzymes that destroy the pathogen. The resulting pathogen debris (termed ‘antigens’) are loaded onto a molecule called “MHC II”, which then presents the antigens to the immune system. This antigen presentation allows for other immune cell types to begin targeting the pathogen.

How Rab17 Works:

The problem is that macrophages also phagocytose cells in our bodies are they are turned over during tissue maintenance. The phagocytosis of these cells – termed ‘efferocytosis’ – must avoid presenting any antigens from these cells, as this results in autoimmune disease. This is where Rab17 gets involved – Rab17 “grabs” the phagosome immediately after it fuses with lysosomes, and redirects the phagosome to fuse with another cellular compartment called the “recycling endosome”. Here, the debris are either absorbed by the macrophage or expelled into the extracellular space, thereby avoiding loading onto MHC II. This allows macrophages to “clean” our tissues of old, damaged and unneeded cells, while preventing autoimmunity.

Reference:

Charles Yin, Dean Argintaru & Bryan Heit (2017). Rab17 mediates intermixing of phagocytosed apoptotic cells with recycling endosomes. Small GTPases. Eprint ahead of publication. [Article] [Pubmed]