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A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex.

ABSTRACT: Autophagy is a cytosolic quality control process that recognizes substrates through receptor-mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR-Cas9 or knockout-mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER-resident lectin chaperone Calnexin (CANX) and the ER-phagy receptor FAM134B are required for autophagy-mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co-receptor that recognizes ER luminal misfolded procollagens and interacts with the ER-phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane-associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome-resistant misfolded clients from the ER.

SUBMITTER: Forrester A

PROVIDER: S-EPMC6331724 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A selective ER-phagy exerts procollagen quality control via a CALNEXIN-FAM134B complex

Project description:Autophagy is a cytosolic quality control process that recognizes substrates through receptor-mediated mechanisms. Procollagens, the most abundant gene products in metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR-Cas9 or knockout-mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER-resident lectin chaperone CALNEXIN (CANX) and the ER-phagy receptor FAM134B are required for autophagy-mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co-receptor that recognizes ER-luminal misfolded procollagens and interacts with the ER-phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane-associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome resistant misfolded clients from the ER.

| S-SCDT-EMBOJ-2018-99847 | biostudies-other

An N-terminal-truncated isoform of FAM134B (FAM134B-2) regulates starvation-induced hepatic selective ER-phagy.

Project description:Autophagy is a conserved system that adapts to nutrient starvation, after which proteins and organelles are degraded to recycle amino acids in response to starvation. Recently, the ER was added to the list of targets of autophagic degradation. Autophagic degradation pathways of bulk ER and the specific proteins sorted through the ER are considered key mechanisms in maintaining ER homeostasis. Four ER-resident proteins (FAM134B, CCPG1, SEC62, and RTN3) have been identified as ER-resident cargo receptors, which contain LC3-interacting regions. In this study, we identified an N-terminal-truncated isoform of FAM134B (FAM134B-2) that contributes to starvation-induced ER-related autophagy. Hepatic FAM134B-2 but not full-length FAM134B (FAM134B-1) is expressed in a fed state. Starvation drastically induces FAM134B-2 but no other ER-resident cargo receptors through transcriptional activation by C/EBPβ. C/EBPβ overexpression increases FAM134B-2 recruitment into autophagosomes and lysosomal degradation. FAM134B-2 regulates lysosomal degradation of ER-retained secretory proteins such as ApoCIII. This study demonstrates that the C/EBPβ-FAM134B-2 axis regulates starvation-induced selective ER-phagy.

| S-EPMC6526285 | biostudies-literature

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 cell homeostasis and function. The recent identification of ER-phagy receptors has shed light on the molecular mechanisms 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 autophagy-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, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER-phagy to respond to both metabolic and developmental cues.

| S-EPMC7459426 | biostudies-literature

MiR-142-5p/FAM134B Axis Manipulates ER-Phagy to Control PRRSV Replication.

Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) can replicate its RNA genome in endoplasmic reticulum (ER) and utilize ER to facilitate its assembly and maturation. To maintain ER homeostasis, host cells initiate reticulophagy (known as ER-phagy) to effectively digest the stressed ER. In this study, we found that PRRSV infection subverted ER-phagy by downregulating ER-phagy receptor FAM134B. PRRSV-induced miR-142-5p directly targeted FAM134B and significantly promoted PRRSV replication. Meanwhile, siRNA-mediated depletion of FAM134B protein and overexpression of FAM134B mutant protein significantly disrupted ER-phagy and facilitated PRRSV replication. Furthermore, our results showed that FAM134B-mediated ER-phagy activated type I interferon signaling to inhibit PRRSV replication. Overall, this study reveals the important role of ER-phagy in PRRSV replication in a FAM134B-dependent manner. Our findings provide an insight into the pathogenesis of PRRSV and offer a theoretical basis for further development of antiviral therapeutic targets.

| S-EPMC9251429 | biostudies-literature

Curvature induction and membrane remodeling by FAM134B reticulon homology domain assist selective ER-phagy.

Project description:FAM134B/RETREG1 is a selective ER-phagy receptor that regulates the size and shape of the endoplasmic reticulum. The structure of its reticulon-homology domain (RHD), an element shared with other ER-shaping proteins, and the mechanism of membrane shaping remain poorly understood. Using molecular modeling and molecular dynamics (MD) simulations, we assemble a structural model for the RHD of FAM134B. Through MD simulations of FAM134B in flat and curved membranes, we relate the dynamic RHD structure with its two wedge-shaped transmembrane helical hairpins and two amphipathic helices to FAM134B functions in membrane-curvature induction and curvature-mediated protein sorting. FAM134B clustering, as expected to occur in autophagic puncta, amplifies the membrane-shaping effects. Electron microscopy of in vitro liposome remodeling experiments support the membrane remodeling functions of the different RHD structural elements. Disruption of the RHD structure affects selective autophagy flux and leads to disease states.

| S-EPMC6542808 | biostudies-literature

Critical roles of FAM134B in ER-phagy and diseases.

Project description:FAM134B (also called JK-1, RETREG1), a member of the family with sequence similarity 134, was originally discovered as an oncogene in esophageal squamous cell carcinoma. However, its most famous function is that of an ER-phagy-regulating receptor. Over the decades, the powerful biological functions of FAM134B were gradually revealed. Overwhelming evidence indicates that its dysfunction is related to pathophysiological processes such as neuropathy, viral replication, inflammation, and cancer. This review describes the biological functions of FAM134B, focusing on its role in ER-phagy. In addition, we summarize the diseases in which it is involved and review the underlying mechanisms.

| S-EPMC7670425 | biostudies-literature

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 cell homeostasis and function. The recent identification of ER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signalling 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 autophagy- 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, that this pathway is activated in chondrocytes by FGF signalling, a critical regulator of skeletal growth. FGF signalling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signalling pathway that allows ER-phagy to respond to both metabolic and developmental cues.

| S-SCDT-EMBOJ-2020-105696P | biostudies-other

FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.

Project description:Degradation of endoplasmic reticulum (ER) 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 oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain-of-function defects, such as hyperactive self-association and membrane scission, which results in excessive ER-phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.

| S-EPMC7049798 | biostudies-literature

A Role for Macro-ER-Phagy in ER Quality Control.

Project description:The endoplasmic-reticulum quality-control (ERQC) system shuttles misfolded proteins for degradation by the proteasome through the well-defined ER-associated degradation (ERAD) pathway. In contrast, very little is known about the role of autophagy in ERQC. Macro-autophagy, a collection of pathways that deliver proteins through autophagosomes (APs) for degradation in the lysosome (vacuole in yeast), is mediated by autophagy-specific proteins, Atgs, and regulated by Ypt/Rab GTPases. Until recently, the term ER-phagy was used to describe degradation of ER membrane and proteins in the lysosome under stress: either ER stress induced by drugs or whole-cell stress induced by starvation. These two types of stresses induce micro-ER-phagy, which does not use autophagic organelles and machinery, and non-selective autophagy. Here, we characterize the macro-ER-phagy pathway and uncover its role in ERQC. This pathway delivers 20-50% of certain ER-resident membrane proteins to the vacuole and is further induced to >90% by overexpression of a single integral-membrane protein. Even though such overexpression in cells defective in macro-ER-phagy induces the unfolded-protein response (UPR), UPR is not needed for macro-ER-phagy. We show that macro-ER-phagy is dependent on Atgs and Ypt GTPases and its cargo passes through APs. Moreover, for the first time the role of Atg9, the only integral-membrane core Atg, is uncoupled from that of other core Atgs. Finally, three sequential steps of this pathway are delineated: Atg9-dependent exit from the ER en route to autophagy, Ypt1- and core Atgs-mediated pre-autophagsomal-structure organization, and Ypt51-mediated delivery of APs to the vacuole.

| S-EPMC4504476 | biostudies-literature

Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress.

Project description:In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo.

| S-EPMC9016075 | biostudies-literature

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