Receptor‐mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy

Ohnstad, Amelia E; Delgado, José A. Delgado; North, Brian J.; Nasa, Isha; Kettenbach, Arminja N.; Schultz, Sebastian W.; Shoemaker, Christopher J.

doi:10.15252/embj.2020104948

Cited by 89 publications

(117 citation statements)

References 85 publications

(107 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, we quantified NBR1 puncta formation in AD microglia after inhibition of miR-17 . NBR1 puncta represent receptor clustering which promotes continued autophagosome formation ( 44 ). Counting puncta labeled with various autophagy proteins is routinely used in autophagy studies to provide a snapshot of this dynamic process ( 45 ).…”

Section: Resultsmentioning

confidence: 99%

“…LC3 accumulation reflects increased presence of autophagosomes, indicating that reducing miR-17 improved both Aβ degradation and autophagy function. NBR1 puncta are indicative of clustering of the NBR1 receptor, which can then promote continued autophagosome formation ( 44 ). These data indicate that miR-17 is a potential therapeutic target in AD which could recover functional autophagy in microglia thus enabling improved Aβ clearance and improved cognition.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

Estfanous

Daily²,

Eltobgy³

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in AD.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

Estfanous

Daily²,

Eltobgy³

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…These data indicate that a fraction of TAX1BP1 can still be degraded during virus infection in the absence of the LC3 lipidation machinery. Two recent studies have described lysosomal degradation pathways involving TAX1BP1 that are independent of ATG7 and LC3 lipidation [42,56]. Future studies should determine if TAX1BP1 is also degraded by these LC3independent lysosomal targeting pathways during RNA virus infection.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of the selective autophagy receptor TAX1BP1 by canonical and noncanonical IκB kinases promotes its lysosomal localization and clearance of MAVS aggregates

Choi

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

TAX1BP1 is a selective autophagy receptor which inhibits NF-κB and RIG-I-like receptor (RLR) signaling to prevent excessive inflammation and maintain homeostasis. Selective autophagy receptors such as p62/SQSTM1 and OPTN are phosphorylated by the noncanonical IκB kinase TBK1 to stimulate their selective autophagy function. However, it is unknown if TAX1BP1 is regulated by TBK1 or other kinases under basal conditions or during RNA virus infection. Here, we found that the noncanonical IκB kinases TBK1 and IKKi phosphorylate TAX1BP1 to regulate its basal turnover, whereas the canonical IκB kinase IKKα and the core autophagy factor ATG9 play essential roles in RNA virus-mediated TAX1BP1 autophagosomal degradation. TAX1BP1 phosphorylation by canonical and noncanonical IκB kinases promotes its localization to lysosomes resulting in its degradation. Furthermore, TAX1BP1 plays a critical role in the clearance of MAVS aggregates, and phosphorylation of TAX1BP1 augments its MAVS aggrephagy function. Together, our data support a model whereby IκB kinases license TAX1BP1 selective autophagy function to inhibit MAVS and RLR signaling.Author SummaryThe RIG-I-like receptor (RLR) pathway induces type I interferon (IFN) and proinflammatory cytokines in response to RNA virus infection. MAVS is a mitochondrial adaptor protein in the RLR pathway that forms prion-like aggregates upon activation; however, how MAVS aggregates are cleared to restore homeostasis is unclear. Autophagy is a lysosomal degradation pathway important for the clearance of potentially cytotoxic protein aggregates that could induce inflammation and/or cell death. TAX1BP1 is a selective autophagy receptor that inhibits RLR signaling, but the precise mechanisms remain unknown. Here, we found that TAX1BP1 is a substrate for multi-site phosphorylation by canonical and noncanonical IκB kinases which triggered its lysosomal localization and degradation. We also found that TAX1BP1 was critical for the clearance of MAVS aggregates in a phosphorylation-dependent manner. Overall, our data suggest that phosphorylation serves a key regulatory function for TAX1BP1 to inhibit RLR signaling.

show abstract

“…LC3, which exists in the form of LC3‐I and LC3‐II2, is the most important protein molecule in autophagy and primarily involved in the formation of autophagosomes 36,37 . Detection of LC3 can reflect the integrity of autophagy flow 38 .…”

Section: Discussionmentioning

confidence: 99%

Phellodendrine promotes autophagy by regulating the AMPK/mTOR pathway and treats ulcerative colitis

Wang

et al. 2021

J Cellular Molecular Medi

View full text Add to dashboard Cite

To investigate the therapeutic effects of phellodendrine in ulcerative colitis (UC) through the AMPK/mTOR pathway. Volunteers were recruited to observe the therapeutic effects of Compound Cortex Phellodendri Liquid (Huangbai liniment). The main components of Compound Cortex Phellodendri Liquid were analysed via network pharmacology. The target of phellodendrine was further analysed. Caco‐2 cells were cultured, and H2O2 was used to stimulate in vitro cell model. Expression levels of LC3, AMPK, p‐AMPK, mTOR and p‐mTOR were detected via Western blotting and through immunofluorescence experiments. The therapeutic effects of phellodendrine were analysed via expression spectrum chip sequencing. The sequencing of intestinal flora further elucidated the therapeutic effects of phellodendrine. Compared with the control group, Compound Cortex Phellodendri Liquid could substantially improve the healing of intestinal mucosa. Network pharmacology analysis revealed that phellodendrine is the main component of Compound Cortex Phellodendri Liquid. Moreover, this alkaloid targets the AMPK signalling pathway. Results of animal experiments showed that phellodendrine could reduce the intestinal damage of UC compared with the model group. Findings of cell experiments indicated that phellodendrine treatment could activate the p‐AMPK /mTOR signalling pathway, as well as autophagy. Expression spectrum chip sequencing showed that treatment with phellodendrine could promote mucosal healing and reduce inflammatory responses. Results of intestinal flora detection demonstrated that treatment with phellodendrine could increase the abundance of flora and the content of beneficial bacteria. Phellodendrine may promote autophagy by regulating the AMPK‐mTOR signalling pathway, thereby reducing intestinal injury due to UC.

show abstract

Receptor‐mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy

Cited by 89 publications

References 85 publications

Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

Phosphorylation of the selective autophagy receptor TAX1BP1 by canonical and noncanonical IκB kinases promotes its lysosomal localization and clearance of MAVS aggregates

Phellodendrine promotes autophagy by regulating the AMPK/mTOR pathway and treats ulcerative colitis

Contact Info

Product

Resources

About