HDLs activate ADAM17‐dependent shedding

Abstract

The tumor necrosis factor-alpha (TNF) converting enzyme (ADAM17) is a metalloprotease that cleaves several transmembrane proteins, including TNF and its receptors (TNFR1 and TNFR2). We recently showed that the shedding activity of ADAM17 is sequestered in lipid rafts and that cholesterol depletion increased the shedding of ADAM17 substrates. These data suggested that ADAM17 activity could be regulated by cholesterol movements in the cell membrane. We investigated if the membrane cholesterol efflux induced by high-density lipoproteins (HDLs) was able to modify the shedding of ADAM17 substrates. HDLs added to different cell types, increased the ectodomain shedding of TNFR2, TNFR1, and TNF, an effect reduced by inhibitors active on ADAM17. The HDLs-stimulated TNF release occurred also on cell-free isolated plasma membranes. Purified apoA1 increased the shedding of TNF in an ABCA1-dependent manner, suggesting a role for the cholesterol efflux in this phenomenon. HDLs reduced the cholesterol and proteins (including ADAM17) content of lipid rafts and triggered the ADAM17-dependent cleavage of TNF in the non-raft region of the membrane. In conclusion, these data demonstrate that HDLs alter the lipid raft structure, which in turn activates the ADAM17-dependent processing of transmembrane substrates.

Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

“…Cholesterol modification and sigma-1 receptor agonist DHEAS could reduce ionomycin-induced ADAM10-dependent BTC shedding but not ADAM17-dependent HB-EGF shedding Cholesterol is a ligand for sigma-1 receptor (Palmer et al, 2007) and its depletion can affect lipid raft formation and both ADAM10-dependent shedding (Murai et al, 2011) and ADAM17-dependent shedding (von Tresckow et al, 2004;Zimina et al, 2005;Tellier et al, 2006Tellier et al, , 2008. Therefore, we tested the effect of cholesterol in our system.…”

“…Those two transmembrane proteases are also involved in the shedding process of many other substrates, such as ligands of the epidermal growth factor receptor (EGFR), Notch1, L1 cell adhesion molecule (L1CAM), which are involved in pathological processes and human diseases such as cancer and stroke (Pruessmeyer and Ludwig, 2009). It is now known that lipid rafts can affect both ADAM17 and ADAM10 function as cholesterol depletion can trigger both ADAM10-mediated CD44 shedding (Murai et al, 2011) and ADAM17-mediated CD30 shedding (von Tresckow et al, 2004), collagen XVII shedding (Zimina et al, 2005), and TNF shedding (Tellier et al, 2006(Tellier et al, , 2008. It has been reported that ADAM10 is located in the nonraft region of the membrane of neuroblastoma SH-SY5Y cells when functioning as α-secretase of APP (Harris et al, 2009) and it cannot cleave APP in a cholesterolrich environment (Kojro et al, 2010).…”

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis

“…33 The integrity of lipid rafts and caveolae, where TACE and TNF-R1 are sequestered in the cell membrane, is critical for efficient TNF-R1 shedding. 34 Disruption of these domains either by incubation with methyl-β-cyclodextrin or by silencing of caveolin-1 has been shown to attenuate the TNF-R1-membrane shedding.…”

Apolipoprotein A-I Inhibits CD40 Proinflammatory Signaling via ATP-Binding Cassette Transporter A1-Mediated Modulation of Lipid Raft in Macrophages

“…To determine the role of ABCA1-mediated cholesterol efflux in apoA-I-induced inhibition of CD40 proinflammatory signaling, we incubated THP-1 macrophages with 300 μM cAMP, which stimulates the synthesis of ABCA1 37) , or with ABCA1 siRNA (ABCA1-/-), which knockdowns ABCA1 protein. As shown in Fig.…”