The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-1 and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insig1 and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor γ (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirt1-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-1α signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.
Collective cell migration is involved in development, wound healing and metastasis. In the
Drosophila
ovary, border cells (BC) form a small cluster that migrates collectively through the egg chamber. To achieve directed motility, the BC cluster coordinates the formation of protrusions in its leader cell and contractility at the rear. Restricting protrusions to leader cells requires the actin and plasma membrane linker Moesin. Herein, we show that the Ste20-like kinase Misshapen phosphorylates Moesin in vitro and in BC. Depletion of Misshapen disrupts protrusion restriction, thereby allowing other cells within the cluster to protrude. In addition, we show that Misshapen is critical to generate contractile forces both at the rear of the cluster and at the base of protrusions. Together, our results indicate that Misshapen is a key regulator of BC migration as it coordinates two independent pathways that restrict protrusion formation to the leader cells and induces contractile forces.
Collective cell migration is not only important for development and
tissue homeostasis but can also promote cancer metastasis. To migrate
collectively, cells need to coordinate cellular extensions and retractions,
adhesion sites dynamics, and forces generation and transmission.
Nevertheless, the regulatory mechanisms coordinating these processes remain
elusive. Using A431 carcinoma cells, we identify the kinase MAP4K4 as a
central regulator of collective migration. We show that MAP4K4 inactivation
blocks the migration of clusters, whereas its overexpression decreases
cluster cohesion. MAP4K4 regulates protrusion and retraction dynamics,
remodels the actomyosin cytoskeleton, and controls the stability of both
cell–cell and cell–substrate adhesion. MAP4K4 promotes focal adhesion
disassembly through the phosphorylation of the actin and plasma membrane
crosslinker moesin but disassembles adherens junctions through a
moesin-independent mechanism. By analyzing traction and intercellular
forces, we found that MAP4K4 loss of function leads to a tensional
disequilibrium throughout the cell cluster, increasing the traction forces
and the tension loading at the cell–cell adhesions. Together, our results
indicate that MAP4K4 activity is a key regulator of biomechanical forces at
adhesion sites, promoting collective migration.
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