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ER-phagy regulates ER dynamics during myogenesis

ABSTRACT: Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, indicates its significance as a regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables an efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER reorganized. Knocking out both FAM134B isoforms in myotubes results in aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Paolo Grumati

LAB HEAD: Paolo Grumati

PROVIDER: PXD053361 | Pride | 2024-12-27

REPOSITORIES: Pride

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			Action	DRS
	2024-06-19_MC_IP_FAM134B1_T10_1.raw	Raw
	2024-06-19_MC_IP_FAM134B1_T10_2.raw	Raw
	2024-06-19_MC_IP_FAM134B1_T10_3.raw	Raw
	2024-06-19_MC_IP_FAM134B1_T10_4.raw	Raw
	2024-06-19_MC_IP_FAM134B1_T2_1.raw	Raw

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ER-phagy regulates ER dynamics during myogenesis

Project description:Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, indicates its significance as a regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables an efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER reorganized. Knocking out both FAM134B isoforms in myotubes results in aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.

2024-12-27 | PXD053358 | Pride

Fam134c and Fam134b shape axonal endoplasmic reticulum architecture in vivo.

Project description:Endoplasmic reticulum (ER) remodeling is vital for cellular organization. ER-phagy, a selective autophagy targeting ER, plays an important role in maintaining ER morphology and function. The FAM134 protein family, including FAM134A, FAM134B, and FAM134C, mediates ER-phagy. While FAM134B mutations are linked to hereditary sensory and autonomic neuropathy in humans, the physiological role of the other FAM134 proteins remains unknown. To address this, we investigated the roles of FAM134 proteins using single and combined knockouts (KOs) in mice. Single KO in young mice showed no major phenotypes, however, combined Fam134b and Fam134c deletion (Fam134b/cdKO), but not the combination including Fam134a deletion, led to rapid neuromuscular and somatosensory degeneration, resulting in premature death. Fam134b/cdKO mice show rapid loss of motor and sensory axons in the peripheral nervous system. Long axons from Fam134b/cdKO mice exhibited expanded tubular ER with a transverse ladder-like appearance, whereas no obvious abnormalities were observed in cortical ER. Our study unveils critical roles of FAM134C and FAM134B in the formation of tubular ER network in axons of both motor and sensory neurons.

2024-06-24 | PXD050983 | Pride

FAM134B oligomerization drives ER membrane scission for ER-phagy

Project description:ER degradation by selective autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomer formation of FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its Reticulon domain was required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER stress conditions, activated CAMK2B phosphorylated the Reticulon domain of FAM134B, which enhanced FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand of ER-phagy. Unexpectedly, FAM134BG216R, a variant derived from a type II HSAN patient, exhibited gain-of-function defects, such as hyperactive self-association and membrane scission, which resulted in excessive ER-phagy and sensory neuron death. Therefore, this study revealed a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggested a potential implication of excessive selective autophagy in human diseases.

2020-01-09 | PXD016661 | Pride

ER-phagy regulates ER dynamics during myogenesis (7)

Project description:Proteomic landscape of Fam134b knockout C2C12 reconstituted with hFAM134B1 or hFAM134B2

2024-12-27 | PXD050907 | Pride

ER-phagy regulates ER dynamics during myogenesis (6)

Project description:Lysosomal isolation and mass spectrometry analysis from wild-type C2C12 myotubes and Fam134bknockout C2C12 myotubes

2024-12-27 | PXD050903 | Pride

ER-phagy regulates ER dynamics during myogenesis

Project description:Proteomic landscape of human myoblasts and differentiated myotubes

2024-12-27 | PXD050898 | Pride

The function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways.

Project description:Selective autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is an important regulator of ER remodeling and is critical to maintaining cellular homeostasis during environmental changes. We recently showed that members of the FAM134 family play a role during stress-induced ER-phagy. However, the mechanisms on how they are activated remain largely unknown. In this study, we analyzed mTOR-mediated phosphorylation of FAM134 as a trigger of FAM134-driven ER-phagy. An unbiased screen of kinase inhibitors revealed that CK2 is essential for ER-phagy driven by FAM134B and FAM134C after inhibition of mTOR. Using superresolution microscopy, we showed that CK2 activity is essential for the formation of high-density groups of FAM134B and FAM134C. Continually, the FAM134B and FAM134C proteins that carry point mutations of selected serine residues within their reticulon homology domain are unable to form high-density clusters. Furthermore, we provide evidence that ubiquitination regulates ER-phagy receptors and that dense clustering of FAM134B and FAM134C requires events upstream of ubiquitination. Treatment with the CK2 inhibitor SGC-CK2-1 or mutation of phosphosites prevents Torin1-induced ER-phagy flux as well as ubiquitination of FAM134 proteins, and consistently treatment with E1 inhibitor suppresses Torin1-induced ER-phagy flux. Therefore, we propose that CK2 dependent phosphorylation of ER-phagy receptors precedes ubiquitin-dependent activation of ER-phagy flux.

2023-11-16 | PXD043003 | Pride

Transcriptional regulation of FAM134B by TFEB/TFE3 controls ER-phagy in response to starvation and chondrocyte differentiation

Project description:Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function1. The recent identification of ER-phagy receptors has shed light on the molecular mechanism underlining this process; however, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3 - master regulators of lysosomal biogenesis and autophagy2- control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. The TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. In addition, we discovered that this pathway is activated in chondrocytes by FGF signaling, a critical regulator of cell differentiation 3. FGF signaling induces a JNK-dependent proteasomal degradation of the insulin receptor substrate 1, which inhibits the insulin-PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and FAM134B induction. Consistent with a role of the TFEB/TFE3-FAM134B axis in chondrocytes, FAM134B knock-down impairs cartilage growth and mineralization in medaka fish. This study identifies a new signaling pathway that allows ER-phagy to respond to both metabolic and developmental cues.

2020-07-15 | PXD015326 | Pride

ER-phagy regulates ER dynamics during myogenesis (4)

Project description:IP-MS interactome of FAM134B1 and FAM134B2 in C2C12 cells differentiated into myotubes

2024-12-27 | PXD050899 | Pride

MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B

Project description:Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of ER homeostasis and function1. The selective incorporation of ER fragments into nascent autophagosomes is facilitated by ER resident proteins, ER-phagy receptors, that bind the autophagosomal LC3 protein via the cytosolic LC3 interacting domain (LIR) (REF). However, the molecular mechanisms that regulate ER-phagy in response to cellular needs are still largely unknown. We found that the MiT/TFE transcription factors - master regulators of lysosomal biogenesis and autophagy2- control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. This pathway is robustly activated in chondrocytes by FGF signaling, a critical regulator of chondrocyte differentiation3. FGF triggers TFEB/TFE3-mediated ER-phagy through JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS-1) protein and inhibition of the insulin signaling. FAM134B knock-down impairs cartilage growth and mineralization in medaka fish, suggesting a physiological role for this process during skeletal growth. Notably, we showed that the TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. Thus, this study identifies MiT/TFE-factors as key transcriptional activators of ER-phagy in response to both metabolic and developmental cues.

2020-07-15 | PXD015130 | Pride

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