A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

Catarino, Steve; Ribeiro-Rodrigues, Teresa; Ferreira, Rita Sá; Ramalho, José S.; Abert, Christine; Martens, Sascha; Girão, Henrique

doi:10.3390/cells9040902

Cited by 5 publications

(5 citation statements)

References 27 publications

(55 reference statements)

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“…Furthermore, we found that LY294002 decreased Cx43 protein levels. This effect may be associated with the fact that when autophagy is induced (such as during hunger), internalized Cx43 will be degraded by autophagy ( Catarino et al, 2020 ). Autophagy has been identified as an important pathway in the degradation of different types of Cxs, and autophagy induced by different factors will directly affect the expression level of Cxs ( Iyyathurai et al, 2016 ; D’hondt et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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Background Oxidized low-density lipoproteins (ox-LDL) may induce foam cell formation from the vascular smooth muscle cell (VSMC) by inhibiting VSMC autophagy. This process accelerates the formation of atherosclerosis (AS). Connexin 43 (Cx43), which is the most widely distributed connexin in VSMC is associated with autophagy. However, the mechanism of action and the involvement of Cx43 in ox-LDL-inhibited VSMC autophagy remain unclear. Methods The primary VSMC were obtained and identified, before primary VSMC were pretreated with an inhibitor (Cx43-specific inhibitor Gap26 and PI3K inhibitor LY294002) and stimulated with ox-LDL. Results Ox-LDL not only inhibited autophagy in VSMC via downregulation of autophagy-related proteins (such as Beclin 1, LC3B, p62), but also increased Cx43 protein levels. Then we added Gap26 to VSMC in the ox-LDL+Gap26 group, in which autophagy-related proteins were increased and the accumulation of lipid droplets was reduced. These result suggested that an enhanced level of autophagy and an alleviation of lipid accumulation might be caused by inhibiting Cx43 in VSMC. The phosphorylation levels of PI3K, AKT, mTOR were increased by ox-LDL, thus down-regulating autophagy-related proteins. However, this situation was partially reversed by the Gap26. Moreover, Cx43 expression were decreased by LY294002 in ox-LDL-induced VSMCs. Conclusion Inhibiting Cx43 may activate VSMC autophagy to inhibit foam cell formation by inhibiting the PI3K/AKT/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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“…Previous studies have found that autophagy leads to the degradation of Cx43 during ischemia, [ 36 ] and gene silencing of autophagy-related genes leads to the accumulation of Cx43 and decreases the co-localization of LC3B and Cx43. [ 37 ] Relevant studies have also shown that during the middle part of M1-type macrophage polarization, autophagy is enhanced, leading to increased degradation of Cx43. [ 38 ] Our results showed that autophagy was increased at 48 hours which led to a decrease of Cx43 at 48 hours (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect of connexin 43 in LPS/IL-4-induced macrophage M1/M2 polarization: An observational study

He,

Dai,

et al. 2024

Medicine

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Lipopolysaccharide (LPS) and interleukin-4 (IL-4) play important roles in inducing M1 and M2 macrophage polarization. Studies have shown that LPS can promote the polarization of macrophages to M1-type and produce many pro-inflammatory cytokines, while IL-4 can promote the polarization of macrophages to M2-type and produce many anti-inflammatory cytokines. Moreover, Connexin 43 (Cx43) is widely expressed in macrophages and has various regulatory functions. However, whether Cx43 is involved in the regulation of macrophage M1/M2 polarization has not been fully studied. This study examined the role of Cx43 and M2 polarization markers using Western blot, immunofluorescence, flow cytometry. Cx43 overexpression was induced using Cx43 overexpressing lentivirus. The statistical software SPSS 20.0 (IBM Corp.) and GraphPad Prism 8.0 (GraphPad Software, La Jolla, CA, United States) were used to analyze the results. P values < .05 were considered to indicate statistically significant differences. Our results showed that LPS promotes the polarization of macrophages to M1-type, which is accompanied by an increase in Cx43 expression from 0 to 24 hours. Moreover, the application of the Cx43-specific blockers Gap19 and Gap26 reduces the expression of macrophage M1-type polarization markers. Thus, the expression of Cx43 increases first, and then, due to the initiation of intracellular autophagy during LPS-induced macrophage M1 polarization. Cx43 is degraded and the expression of Cx43 decreases from 24 hours to 48 hours. IL-4 decreases the expression of Cx43 from 24 hours to 48 hours and promotes the transformation of macrophages to M2-type. The application of Cx43 overexpression lentivirus leads to a reduction in the expression of M2 polarization markers. IL-4-induced M2 polarization of macrophages inhibits cell autophagy, reducing Cx43 degradation and leading to an increase in Cx43 from 24 hours to 48 hours. Thus, Cx43 expression in M2-type polarization experiences a reduction at first and then an increase from 24 hours to 48 hours. The direction of macrophage polarization can be controlled by regulating the expression of Cx43, thus providing a theoretical basis for treating atherosclerosis, tumors, and other diseases associated with macrophage polarization.

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“…On the contrary, unconventional secretion of cytosolic proteins could also take place to prevent PTMs that can inactivate them as seen in the case of unconventional secretion of FGF2 which prevents its O-glycosylation that makes it biologically inactive (Wegehingel et al, 2008). Similarly, in another example, it is reported that the conserved LIR motif in connexins mediate the ubiquitin independent binding to the autophagic proteins of LC3 (Catarino et al, 2020). Likewise, the specific phosphorylation of the small heat shock protein, α-Crystallin B at the Ser59 residue enhances autophagy mediated secretion (D'Agostino et al, 2019).…”

Section: Key Research Perspectivesmentioning

confidence: 99%

Facets of Autophagy Based Unconventional Protein Secretion–The Road Less Traveled

Padmanabhan

Manjithaya

2020

Front. Mol. Biosci.

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Unconventional protein secretion (UCPS) of leaderless proteins bypasses the conventional endoplasmic reticulum (ER)-Golgi route. The proportion of UCPS in the secretome varies tremendously across eukaryotes. Interestingly, macroautophagy, an intracellular recycling process that is generally involved in cargo degradation, also participates in UCPS. This emerging field of secretory mode of autophagy is underexplored and has several unanswered questions regarding the composition of players, cargo, and the mechanisms that drive it. As secretomes vary considerably across cell types and physiological conditions, the contribution of secretory autophagy in healthy and pathophysiological states remain to be elucidated. Recent studies have begun to shed light on this enigmatic process.

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A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

Cited by 5 publications

References 27 publications

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Effect of connexin 43 in LPS/IL-4-induced macrophage M1/M2 polarization: An observational study

Facets of Autophagy Based Unconventional Protein Secretion–The Road Less Traveled

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