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2014 ; 10
(11
): 1937-52
Nephropedia Template TP
Giegerich AK
; Kuchler L
; Sha LK
; Knape T
; Heide H
; Wittig I
; Behrends C
; Brüne B
; von Knethen A
Autophagy
2014[]; 10
(11
): 1937-52
PMID25483963
show ga
Lipopolysaccharide (LPS)-induced activation of TLR4 (toll-like receptor 4) is
followed by a subsequent overwhelming inflammatory response, a hallmark of the
first phase of sepsis. Therefore, counteracting excessive innate immunity by
autophagy is important to contribute to the termination of inflammation. However,
the exact molecular details of this interplay are only poorly understood. Here,
we show that PELI3/Pellino3 (pellino E3 ubiquitin protein ligase family member
3), which is an E3 ubiquitin ligase and scaffold protein in TLR4-signaling, is
impacted by autophagy in macrophages (M?) after LPS stimulation. We noticed an
attenuated mRNA expression of proinflammatory Il1b (interleukin 1, ?) in Peli3
knockdown murine M? in response to LPS treatment. The autophagy adaptor protein
SQSTM1/p62 (sequestosome 1) emerged as a potential PELI3 binding partner in
TLR4-signaling. siRNA targeting Sqstm1 and Atg7 (autophagy related 7),
pharmacological inhibition of autophagy by wortmannin as well as blocking the
lysosomal vacuolar-type H(+)-ATPase by bafilomycin A1 augmented PELI3 protein
levels, while inhibition of the proteasome had no effect. Consistently, treatment
to induce autophagy by MTOR (mechanistic target of rapamycin (serine/threonine
kinase)) inhibition or starvation enhanced PELI3 degradation and reduced
proinflammatory Il1b expression. PELI3 was found to be ubiquitinated upon LPS
stimulation and point mutation of PELI3-lysine residue 316 (Lys316Arg) attenuated
Torin2-dependent degradation of PELI3. Immunofluorescence analysis revealed that
PELI3 colocalized with the typical autophagy markers MAP1LC3B/LC3B
(microtubule-associated protein 1 light chain 3 ?) and LAMP2
(lysosomal-associated membrane protein 2). Our observations suggest that
autophagy causes PELI3 degradation during TLR4-signaling, thereby impairing the
hyperinflammatory phase during sepsis.
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