Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms

Abstract

The role of N 6 -methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterized the role of N 6 -adenosine-methyltransferase-like 3 (METTL3), whose expression is elevated in renal tubules in different acute kidney injury (AKI) models as well as in human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated renal inflammation and programmed cell death in TECs in response to stimulation by tumor necrosis factor–α (TNF-α), cisplatin, and lipopolysaccharide (LPS), whereas METTL3 overexpression had the opposite effects. Conditional knockout of METTL3 from mouse kidneys attenuated cisplatin- and ischemic/reperfusion (I/R)–induced renal dysfunction, injury, and inflammation. Moreover, TAB3 [TGF-β–activated kinase 1 (MAP3K7) binding protein 3] was identified as a target of METTL3 by m6A methylated RNA immunoprecipitation sequencing and RNA sequencing. The stability of TAB3 was increased through binding of IGF2BP2 (insulin-like growth factor 2 binding protein 2) to its m6A-modified stop codon regions. The proinflammatory effects of TAB3 were then explored both in vitro and in vivo. Adeno-associated virus 9 (AAV9)–mediated METTL3 silencing attenuated renal injury and inflammation in cisplatin- and LPS-induced AKI mouse models. We further identified Cpd-564 as a METTL3 inhibitor that had better protective effects against cisplatin- and ischemia/reperfusion-induced renal injury and inflammation than S -adenosyl- l -homocysteine, a previously identified METTL3 inhibitor. Collectively, METTL3 promoted m6A modifications of TAB3 and enhanced its stability via IGF2BP2-dependent mechanisms. Both genetic and pharmacological inhibition of METTL3 attenuated renal injury and inflammation, suggesting that the METTL3/TAB3 axis is a potential target for treatment of AKI.

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…regulate the development of multiple diseases (e.g., tumor and kidney injury) through glycan metabolism. [ 103 , 104 ], and these pathogenic mechanisms involve different signaling pathways (GLUT1-mTORC1 axis, TRAF6/NF-κB and NF-κB/MAPK pathways). For example, METTL3 promotes colorectal cancer by activating the m6A-GLUT1-mTORC1 axis [ 104 ]; YTHDF2 mediates lipopolysaccharide-induced osteoclastogenesis and inflammatory response via the NF-κB and MAPK signaling pathways [ 105 ].…”

RNA binding protein IGF2BP1 meditates oxidative stress-induced granulosa cell dysfunction by regulating MDM2 mRNA stability in an m6A-dependent manner

“…Having demonstrated that cell cycle dysregulation is one of the pivotal mechanisms underlying GCs damages, we reasoned that a cell cycle regulating factor might be involved in this process. Previous studies have revealed that IGF2BPs, an RNA-binding protein family facilitating to stabilize its target RNAs [ [15] , [16] , [17] , [18] ], play a key role in controlling cell cycle and regulating cancer cell proliferation [ 20 , [41] , [42] , [43] ]. IGF2BPs knockdown or depletion impaired cell cycle progression and limited tumor growth [ 20 , 41 ].…”

“…In this study, we found the treatment of 3-nitropropionic acid (3-NP), a mitochondrial toxin inducing intracellular OS by targeting complex II of electron transport chain, led to significant downregulation of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and subsequently resulted in MDM2 mRNA instability in GCs. IGF2BP1 is an RNA-binding protein which preferentially binds to m 6 A modifications and helps to stabilize its targeted transcripts [ [15] , [16] , [17] , [18] ]. As a potent oncogenic factor, IGF2BP1 regulates proliferation, cell cycle progression and stemness of cancer cells [ 17 , 19 , 20 ].…”

METTL3 Attenuates Inflammation in Fusarium solani–Induced Keratitis via the PI3K/AKT Signaling Pathway

“…Moreover, knockdown of METTL3 attenuated renal inflammation and programmed cell death in tubular epithelial cells. 13 Notably, our previous research revealed that significantly increased levels of METTL3 in the corneal tissue of F. solani -infected mice. 14 However, the molecular pathway and mechanism of the function of METTL3 in FK has not been well elucidated.…”