Affinage

RETREG2

Reticulophagy regulator 2 · UniProt Q8NC44

Length
543 aa
Mass
57.8 kDa
Annotated
2026-06-10
42 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RETREG2 (FAM134A) is an endoplasmic reticulum-resident ER-phagy receptor that drives ER fragmentation and lysosomal degradation of ER membrane upon autophagy induction or ER stress (PMID:34338405). It maintains ER morphology through its LC3-interacting region (LIR), but can also act LIR-independently to compensate for loss of its paralogues FAM134B and FAM134C in degrading the shared ER-phagy substrate pro-Collagen I (PMID:34338405). This receptor activity has disease relevance: RETREG2 variants modulate ER-phagy-mediated clearance of the misfolded α1-antitrypsin variant Z in iPSC-derived hepatocytes, positioning RETREG2 as a modifier of hepatic proteotoxicity in α1-antitrypsin deficiency (PMID:38557779). RETREG2 expression is controlled epigenetically through a SIRT1–BRD4/G9a axis that regulates XBP1s-dependent transcription, and its loss compromises ER-phagy and promotes neuronal death, while its restoration is protective (PMID:40959274). Beyond its canonical ER-phagy role, RETREG2 was independently characterized in lung cancer (as MAG-2) where it promotes proliferation and invasion in association with elevated intracellular calcium, MMP-2, and CD44 (PMID:19212629, PMID:20735960), and is required for normal mitotic progression and intracellular pressure generation (PMID:29097687); how these activities connect to its ER-phagy receptor function is not resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Low

    Established the existence and genomic structure of the gene (then MAG-2) and its first functional association — differential expression correlating with metastatic potential — before any molecular role was known.

    Evidence Suppression subtractive hybridization and gene chip screening of metastatic lung cancer cell sublines

    PMID:21310131

    Open questions at the time
    • No direct functional experiment
    • Correlative expression only, no causal mechanism
  2. 2008 Low

    Tested whether the gene actively drives a cancer phenotype, showing gain/loss of function alters proliferation alongside changes in PCNA, p53, and intracellular calcium.

    Evidence Sense/antisense stable transfection in PLA801 lung cancer cells with proliferation, RT-PCR, Western, and calcium imaging readouts

    PMID:20735960

    Open questions at the time
    • Single lab, non-peer-reviewed journal
    • Mechanism linking calcium to proliferation not defined
    • No connection yet to ER biology
  3. 2009 Medium

    Extended the cancer phenotype to invasion/metastasis, linking the gene to MMP-2, CD44, and intracellular calcium through bidirectional perturbation.

    Evidence Overexpression and RNAi in lung cancer cells with invasion/migration assays and molecular readouts

    PMID:19212629

    Open questions at the time
    • No independent replication
    • Mechanistic link between the gene and MMP-2/CD44 induction unresolved
    • Relationship to later-defined ER-phagy role unknown
  4. 2017 Medium

    Localized the protein to the ER and revealed a role in cell division, where depletion impairs metaphase plate alignment and intracellular pressure via cortical myosin II delocalization.

    Evidence Genome-scale RNAi screen with microcantilever single-cell mechanical phenotyping and fluorescence localization

    PMID:29097687

    Open questions at the time
    • No rescue or mutagenesis to confirm specificity
    • Mechanism connecting ER localization to mitotic pressure unclear
    • Not linked to ER-phagy function
  5. 2021 High

    Defined the protein's core molecular identity as a LIR-dependent ER-phagy receptor that fragments ER for lysosomal degradation, and uniquely can substitute LIR-independently for its paralogues in degrading pro-Collagen I.

    Evidence Knockout and overexpression cell lines, global proteomics, ER-phagy flux assays, LIR mutants, and collagen I substrate degradation assays

    PMID:34338405

    Open questions at the time
    • Mechanism of LIR-independent substrate degradation undefined
    • Atg8-family binding preference not directly measured for this protein
    • No structural model
  6. 2024 Medium

    Demonstrated disease-relevant ER-phagy function, showing the protein's variants modify clearance of misfolded α1-antitrypsin variant Z in human hepatocytes.

    Evidence Patient family genomic sequencing and iPSC-derived hepatocyte degradation kinetics with patient-specific variants

    PMID:38557779

    Open questions at the time
    • Single study
    • Molecular basis of variant effects on receptor activity not resolved
    • Interaction with MTMR12 variant mechanistically unexplained
  7. 2024 Medium

    Defined the in vivo functional boundary, establishing through genetic epistasis that this protein cannot compensate for combined FAM134B/FAM134C loss in maintaining axonal tubular ER architecture.

    Evidence Single and combined knockout mice with neuromuscular phenotyping and electron microscopy of axonal ER

    PMID:39039299

    Open questions at the time
    • Why compensation fails in axons but succeeds for collagen is unexplained
    • Tissue-specific contribution of the protein not isolated
    • Single study
  8. 2025 Medium

    Identified an upstream regulatory axis controlling protein expression, showing a SIRT1–BRD4/G9a chromatin pathway gates XBP1s-dependent transcription and that restoring the protein rescues ER-phagy and neuronal survival.

    Evidence ChIP for histone marks and BRD4/G9a, SIRT1 activity assays, overexpression rescue, and BRD4 inhibitor treatment in cells and ethanol-fed mice

    PMID:40959274

    Open questions at the time
    • Single lab study
    • Direct contribution of restored ER-phagy versus other effects to neuroprotection not dissected
    • Generality beyond ethanol context untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the protein's cancer-associated activities (calcium modulation, MMP-2/CD44, invasion) and its mitotic role mechanistically relate to its ER-phagy receptor function remains unresolved.
  • No experiment connects ER-phagy activity to the cancer readouts
  • Mechanism of intracellular calcium modulation undefined
  • No structural or biochemical model of substrate selection

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-9612973 Autophagy 3

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 FAM134A (RETREG2) functions as an ER-phagy receptor that, upon autophagy induction or ER stress, induces ER fragmentation and subsequent lysosomal degradation. FAM134A maintains ER morphology in a LC3-interacting region (LIR)-dependent manner. Notably, FAM134A can act in a LIR-independent manner to compensate for loss of FAM134B and FAM134C in degrading pro-Collagen I as a shared ER-phagy substrate, whereas FAM134C cannot compensate for loss of its paralogues. Overexpression and knockout cell lines with global proteomic analysis, ER-phagy flux assays, LIR-mutant constructs, collagen I substrate degradation assays EMBO reports High 34338405
2017 FAM134A (RETREG2) is localized to the endoplasmic reticulum, and its depletion by RNAi impairs mitotic progression by affecting metaphase plate alignment and intracellular pressure generation, the latter through delocalization of cortical myosin II. Genome-scale RNAi screen with microcantilever-based single-cell mechanical phenotyping; protein localization by fluorescence microscopy; measurement of mitotic rounding force, pressure, and volume Nature communications Medium 29097687
2021 FAM134B (the closest paralogue) preferentially binds the GABARAP subfamily of Atg8 proteins over the LC3 subfamily via its LIR motif plus a C-terminal helix, and structural analysis suggests these binding properties are conserved in FAM134A. Crystal structure of FAM134B-GABARAP complex; binding affinity measurements; inference extended to FAM134A by sequence/structural conservation analysis FEBS open bio Low 34854256
2022 FAM134C (a paralogue) is phosphorylated by casein kinase 2 (CK2) at residues flanking its LIR domain under fed conditions, reducing LC3-binding affinity and suppressing ER-phagy; mTORC1 inhibition during starvation limits CK2-mediated phosphorylation, thereby activating FAM134C-dependent ER-phagy. This phosphorylation-based activation mechanism is specific to FAM134C and not described for FAM134A. Phospho-mutagenesis, CK2 kinase assays, LC3 binding affinity measurements, FAM134C knockout mice, in vivo ER-phagy reporter Science advances Low 36044577
2024 FAM134A (RETREG2) variants can accelerate degradation of misfolded α1-antitrypsin variant Z in iPSC-derived hepatocyte-like cells, while a specific FAM134A variant combined with an MTMR12 variant slows this degradation, implicating FAM134A-mediated ER-phagy as a modifier of hepatic proteotoxicity in α1-antitrypsin deficiency. Genomic sequencing of patient families; iPSC-derived hepatocyte-like cell assays measuring α1-antitrypsin variant Z degradation kinetics with patient-specific variants Hepatology Medium 38557779
2009 MAG-2 (identified as FAM134A/RETREG2 in the lung cancer context) promotes invasion, mobility, and adherence of lung cancer cells, with overexpression upregulating MMP-2 and CD44 expression and increasing intracellular free calcium ion concentration, while knockdown reduces these metastatic properties. Gene transfection (overexpression) and RNAi (knockdown) in lung cancer cells; invasion/migration assays; RT-PCR and Western blot for MMP-2 and CD44; Fluo-3-AM calcium imaging Oncology reports Medium 19212629
2008 MAG-2 (FAM134A/RETREG2) promotes lung cancer cell proliferation by increasing PCNA mRNA levels, downregulating p53 protein, and elevating intracellular cytoplasmic free calcium concentration; knockdown decreases calcium levels and restrains proliferation. Stable transfection of sense/antisense MAG-2 vectors in PLA801 cells; MTT proliferation assay; RT-PCR for PCNA; Western blot for p53; Fluo-3-AM calcium staining; cell cycle analysis Zhongguo fei ai za zhi = Chinese journal of lung cancer Low 20735960
2024 FAM134A and FAM134B are dispensable individually, but combined deletion of FAM134B and FAM134C (not FAM134A) in mice causes rapid neuromuscular degeneration and death, with loss of motor and sensory axons and expanded tubular ER with ladder-like appearance in long axons; FAM134A cannot compensate for combined FAM134B/FAM134C loss in axonal ER architecture. Single and combined knockout mice; neuromuscular phenotyping; electron microscopy of axonal ER morphology; histology of peripheral nervous system EMBO reports Medium 39039299
2025 Ethanol reduces FAM134A expression in neuronal cells and mouse hippocampus through an epigenetic mechanism: ethanol metabolism suppresses SIRT1 activity, leading to increased H4K16 acetylation, enhanced BRD4 recruitment to the FAM134A promoter, and BRD4/G9a complex-mediated H3K9 dimethylation that blocks XBP1s-dependent transcription of FAM134A. BRD4 inhibition or FAM134A overexpression restores ER-phagy and prevents synaptic loss and neuronal death. ChIP assays for histone marks and BRD4/G9a at FAM134A promoter; SIRT1 activity assays; FAM134A overexpression rescue; BRD4 inhibitor treatment in cells and ethanol-fed mice; cognitive function testing International journal of biological sciences Medium 40959274
2003 MAG-2 (subsequently identified as FAM134A/RETREG2) was identified as a gene with a 9-exon, 5.2 kb structure located on chromosome 2q35, showing higher expression in high-metastatic versus low-metastatic lung cancer cell sublines derived from the same parental line. Suppression subtractive hybridization (SSH) library construction and gene chip screening; sequencing and GenBank analysis; ORF and structural prediction Zhongguo fei ai za zhi = Chinese journal of lung cancer Low 21310131

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Tumor targeting by an aptamer. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 294 16595502
2018 Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A. Proceedings of the National Academy of Sciences of the United States of America 210 29440427
2021 Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control. EMBO reports 97 34338405
2007 Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. Schizophrenia research 90 17964117
1994 Activity of two synthetic amphiphilic peptides and magainin-2 against herpes simplex virus types 1 and 2. International journal of peptide and protein research 54 7928088
2017 Genome-scale single-cell mechanical phenotyping reveals disease-related genes involved in mitotic rounding. Nature communications 50 29097687
1991 Identification and characterization of a new gene family induced during macrophage activation. Journal of immunology (Baltimore, Md. : 1950) 47 1753106
1986 Jimpy mice: quantitation of myelin-associated glycoprotein and other proteins. Journal of neurochemistry 47 2423646
2002 Murine GBP-5, a new member of the murine guanylate-binding protein family, is coordinately regulated with other GBPs in vivo and in vitro. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 46 12396730
1993 Phylogenetic relationships of reverse transcriptase and RNase H sequences and aspects of genome structure in the gypsy group of retrotransposons. Molecular biology and evolution 46 7506345
1993 The T-lymphocyte response against myelin-associated glycoprotein and myelin basic protein in patients with multiple sclerosis. Neurology 40 7679782
2009 99mTcO(MAG2-3G3-dimer): a new integrin alpha(v)beta(3)-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics. European journal of nuclear medicine and molecular imaging 37 19484236
1978 Lysosomal phospholipids from rat liver after treatment with different drugs. Hoppe-Seyler's Zeitschrift fur physiologische Chemie 37 627402
1988 Comparative immunocytochemistry of Pelizaeus-Merzbacher disease, the jimpy mouse, and the myelin-deficient rat. Journal of the neurological sciences 34 2454299
1997 Sex differences in function of a pheromonally stimulated pathway: role of steroids and the main olfactory system. Brain research bulletin 32 9370205
2022 Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy. Science advances 30 36044577
2007 Global phenotype screening and transcript analysis outlines the inhibitory mode(s) of action of two amphibian-derived, alpha-helical, cationic peptides on Saccharomyces cerevisiae. Antimicrobial agents and chemotherapy 27 17846143
2012 Evaluation of 188Re-MAG2-RGD-bombesin for potential prostate cancer therapy. Nuclear medicine and biology 16 23199569
2023 A homozygous missense mutation in the fibroblast growth factor 5 gene is associated with the long-hair trait in Angora rabbits. BMC genomics 14 37268908
2021 Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility. Scientific reports 13 33504897
2022 Osteoclast-derived extracellular miR-106a-5p promotes osteogenic differentiation and facilitates bone defect healing. Cellular signalling 12 36464103
2022 The antimicrobial peptide Magainin-2 interacts with BamA impairing folding of E. coli membrane proteins. Frontiers in chemistry 10 36324521
2021 The crystal structure of the FAM134B-GABARAP complex provides mechanistic insights into the selective binding of FAM134 to the GABARAP subfamily. FEBS open bio 10 34854256
2018 Human Liver Fatty Acid Binding Protein-1 T94A Variant, Nonalcohol Fatty Liver Disease, and Hepatic Endocannabinoid System. Lipids 10 29488637
2021 Ag/AgCl@MIL-88A(Fe) heterojunction ternary composites: towards the photocatalytic degradation of organic pollutants. Dalton transactions (Cambridge, England : 2003) 9 33544106
2009 MAG-2 promotes invasion, mobility and adherence capability of lung cancer cells by MMP-2, CD44 and intracellular calcium in vitro. Oncology reports 9 19212629
2024 Fam134c and Fam134b shape axonal endoplasmic reticulum architecture in vivo. EMBO reports 7 39039299
1995 Inactivation of Food-borne Pathogens with Magainin Peptides a. Journal of food protection 7 31137349
2013 Acyl migration evaluation in monoacylglycerols from Echium plantagineum seed oil and Marinol. Journal of bioscience and bioengineering 6 23287502
2025 A comprehensive pan-cancer analysis of RNF187 in human tumors. Discover oncology 5 39804497
2024 Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency. Hepatology (Baltimore, Md.) 5 38557779
2022 2-Arachidonoyl glycerol suppresses gastric emptying via the cannabinoid receptor 1-cholecystokinin signaling pathway in mice. Lipids 5 35266554
2021 2-Arachidonoyl glycerol potently induces cholecystokinin secretion in murine enteroendocrine STC-1 cells via cannabinoid receptor CB1. Lipids 5 34533218
2023 Andean soil-derived lignocellulolytic bacterial consortium as a source of novel taxa and putative plastic-active enzymes. Systematic and applied microbiology 4 38211536
1991 A human monoclonal IgG reactive with a private idiotope of a monoclonal IgM with autoantibody activity against myelin-associated glycoprotein. European journal of immunology 4 1708339
1996 mRNA levels for central nervous system myelin proteins in myelin deficiency of caprine beta-mannosidosis. Brain research. Developmental brain research 3 8821484
2023 Peptide grafting on intraosseous transcutaneous amputation prostheses to promote sealing with skin cells: Potential to limit infections. Journal of biomedical materials research. Part A 1 36680491
2026 ER-phagy receptors: structural mechanisms in selective ER degradation and disease implications. Acta pharmacologica Sinica 0 41593210
2025 Recovery of FAM134A-mediated ER-phagy through BRD4 inhibition alleviates ethanol-induced neurodegeneration. International journal of biological sciences 0 40959274
2025 Structure of a barrel-stave pore formed by magainin-2 reveals anion selectivity and zipper-mediated assembly. Scientific reports 0 41233432
2008 [The proliferation promoting effects of MAG-2 on human lung cancer cell PLA801.]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 20735960
2003 [Identification of novel metastasis associated genes MAG-1 and MAG-2]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 21310131

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