RT Journal Article
SR Electronic
T1 PIKfyve deficiency in myeloid cells impairs lysosomal homeostasis in macrophages and promotes systemic inflammation in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 610683
DO 10.1101/610683
A1 Sang Hee Min
A1 Aae Suzuki
A1 Lehn Weaver
A1 Jessica Guzman
A1 Liang Zhao
A1 Francina Gonzalez
A1 Lynn A. Spruce
A1 Steven H. Seeholzer
A1 Edward Behrens
A1 Charles S. Abrams
YR 2019
UL http://biorxiv.org/content/early/2019/04/16/610683.abstract
AB Macrophages are professional phagocytes that are essential for host defense and tissue homeostasis. Proper membrane trafficking and degradative functions of the endolysosomal system is known to be critical for the function of these cells. We have found that PIKfyve, the kinase that synthesizes the endosomal phosphoinositide PI(3,5)P2, is an essential regulator of lysosomal biogenesis and degradative functions in macrophages. Genetically engineered mice lacking PIKfyve in their myeloid cells (PIKfyvefl/fl LysM-Cre) develop diffuse tissue infiltration of foamy macrophages, hepatosplenomegaly, and systemic inflammation. PIKfyve loss in macrophages causes enlarged endolysosomal compartments and impairs the lysosomal degradative function. Moreover, PIKfyve deficiency increases the cellular levels of lysosomal proteins. Although PIKfyve deficiency reduced the activation of mTORC1 pathway and was associated with increased cleavage of TFEB proteins, this does not translate into transcriptional activation of lysosomal genes, suggesting that PIKfyve modulates the abundance of lysosomal proteins by affecting the degradation of these proteins. Taken together, our study shows that PIKfyve modulation of lysosomal degradative activity and protein expression is essential to maintain lysosomal homeostasis in macrophages.