| Finding/Concept | Evidence type (primary/review/genetics) | Experimental system/assay | Key quantitative/statistical detail | Implication for function | Source with DOI/year/URL |
|---|---|---|---|---|---|
| **Identity and core function of RETREG2/FAM134A (Q8NC44)**: FAM134A is an ER-resident FAM134/RETREG-family protein and a functional ER-phagy receptor | Primary | U2OS overexpression, HA-tag localization with CALNEXIN/REEP5, GST–mATG8 pull-downs, LC3B colocalization, immunogold EM, ssRFP-GFP-KDEL ER-phagy reporter, Fam134 KO/reconstitution in MEFs | FAM134A binds all six mammalian ATG8s via its LIR; starvation increases LC3B+/HA+ ER fragments; wild-type but not ΔLIR is efficiently delivered to lysosomal/LAMP1+ structures; ER-phagy flux induction is milder than FAM134B, consistent with lower basal activity (pqac-00000016, pqac-00000038) | Confirms RETREG2/FAM134A as a stress-activated ER-phagy receptor linking ER membrane remodeling to lysosomal degradation | Reggio et al., **EMBO Reports** (Aug 2021), doi:10.15252/embr.202052289, https://doi.org/10.15252/embr.202052289 (pqac-00000014, pqac-00000016, pqac-00000038) |
| **RETREG2 helps maintain ER morphology and ER proteostasis** | Primary | Single Fam134a/b/c KO MEFs, global proteomics, immunolabeling for ER markers and Collagen I, rescue with WT or ΔLIR constructs | KO cells accumulate ER proteins and collagen-related proteins; swollen/dilated ER with expanded CLIMP63/CANX-positive regions is rescued by WT Fam134 proteins but not by LIR-defective rescue for morphology assays (pqac-00000012, pqac-00000013) | RETREG2 contributes to ER size/shape control and selective ER turnover, not merely cargo binding | Reggio et al., **EMBO Reports** (2021), doi:10.15252/embr.202052289, https://doi.org/10.15252/embr.202052289 (pqac-00000012, pqac-00000013) |
| **RETREG2 has a distinct, partly LIR-independent role in procollagen quality control** | Primary | Fam134a KO and Fam134b KO MEFs; reconstitution with WT vs ΔLIR Fam134a; lysosome localization of procollagen; LC3B/GABARAP interaction assays | ΔLIR Fam134a was as effective as WT Fam134a in reducing pro-Collagen I accumulation in Fam134a KO MEFs; endogenous LC3B interaction is weak, with slight GABARAP interaction; FAM134A can compensate for loss of FAM134B/C in procollagen clearance (pqac-00000015) | Suggests RETREG2 can mediate clearance of misfolded procollagen via a parallel pathway that is less dependent on canonical LC3/LIR engagement than FAM134B/C | Reggio et al., **EMBO Reports** (2021), doi:10.15252/embr.202052289, https://doi.org/10.15252/embr.202052289 (pqac-00000015) |
| **Family-level ER-phagy mechanism and receptor context** | Review | Physiological synthesis of mammalian ER-phagy pathways | FAM134-family proteins are established ER-phagy receptors; RHD-containing receptors deform ER membranes before scission; FAM134 proteins interact with calnexin to help segregate misfolded luminal clients for ER subdomain clearance (pqac-00000004, pqac-00000008) | Places RETREG2 in the current accepted framework: membrane-shaping ER-phagy receptor acting in selective ER quality control | Reggiori & Molinari, **Physiological Reviews** (Jul 2022), doi:10.1152/physrev.00038.2021, https://doi.org/10.1152/physrev.00038.2021 (pqac-00000004, pqac-00000008) |
| **2023 mechanistic advance: phosphorylation→ubiquitination→cluster activation in the FAM134 family** | Primary, family mechanism | Torin1-induced ER-phagy, kinase-inhibitor screen, CK2 inhibition, mass spectrometry, phospho-mutants, TUBE2 ubiquitin pulldown, DNA-PAINT/SMLM, ssRFP-GFP-KDEL reporter | Torin1-induced ER-phagy was ~3-fold higher in FAM134B/C-overexpressing cells than control; E1 inhibition reduced flux by >80%; CK2 inhibition reduced Torin1-induced ER-phagy by ~60–70%; FAM134B cluster mode shifted from **66 nm** basal to **104 nm** after Torin1, blocked by CK2 inhibition (**69 nm**) or phospho-mutant (**63–65 nm**) (pqac-00000027, pqac-00000042, pqac-00000048) | Direct data are for FAM134B/C, but they define an important current mechanistic model for activation of stress-inducible FAM134-family ER-phagy receptors; RETREG2 is likely interpreted within this family framework, though not directly proven here | Berkane et al., **Nature Communications** (Oct 2023), doi:10.1038/s41467-023-44101-5, https://doi.org/10.1038/s41467-023-44101-5 (pqac-00000024, pqac-00000027, pqac-00000042, pqac-00000048) |
| **2023 mechanistic advance: heteromeric ubiquitinated ER-shaping clusters; ARL6IP1 interacts with FAM134A** | Primary | Co-immunoprecipitation, BiCAP heterodimer assays, LC–MS interactomics, KO mice, patient/KO cells, EM/ER morphology analyses | Tagged FAM134A co-immunoprecipitates with ARL6IP1; interactome partitioning: **7%** ARL6IP1-unique, **52.4%** FAM134B-unique, ~**40%** shared partners; Arl6ip1 KO mice showed reduced brain weight (**0.46 g WT vs 0.39 g KO, P=0.016**), reduced CMAPs (**F=18.6, P=0.0015**), and increased ER sheet area (**P=0.0006**) (pqac-00000019, pqac-00000047) | Supports a model in which RETREG2/FAM134A participates in higher-order ER-shaping/ER-phagy assemblies rather than acting alone; links the pathway to neurodegenerative phenotypes | Foronda et al., **Nature** (May 2023), doi:10.1038/s41586-023-06090-9, https://doi.org/10.1038/s41586-023-06090-9 (pqac-00000019, pqac-00000047) |
| **2024 in vivo advance: FAM134 paralogue redundancy is tissue-specific; FAM134B/C dominate axonal ER maintenance** | Primary | Single and double knockout mice, electrophysiology, behavioral phenotyping, nerve ultrastructure, proteomics | Fam134b/c double KO caused severe early neurodegeneration and lifespan <~**25 weeks**; Fam134c KO increased nociceptive firing (**4.107 ± 0.599 spikes/s vs 0.40 ± 0.053 WT, P=0.0455**) and burst frequency (**34.586 ± 5.385 Hz vs 4.572 ± 0.313 WT, P<0.0001**); ~**75%** of axons in Fam134b/cdKO were intermediate/accumulated at 4 weeks; Fam134a was low/absent in sciatic nerve and did not substitute effectively in the double-KO phenotype (pqac-00000033, pqac-00000034, pqac-00000035) | Indicates RETREG2/FAM134A is not the dominant paralogue in peripheral axons, underscoring paralogue specialization despite shared ER-phagy architecture | Iavarone et al., **EMBO Reports** (Jul 2024), doi:10.1038/s44319-024-00213-7, https://doi.org/10.1038/s44319-024-00213-7 (pqac-00000032, pqac-00000033, pqac-00000034, pqac-00000035) |
| **Human genetics relevance: RETREG2/FAM134A prioritized as a novel glioma susceptibility gene** | Genetics | Transcriptome-wide Mendelian randomization + colocalization integrating eQTL and glioma GWAS | Analysis used brain eQTL **n=1,194**, blood eQTL **n=31,684**, and glioma GWAS **7,400 cases / 8,257 controls** (GBM **3,112**; non-GBM **2,411**); RETREG2/FAM134A emerged among **3 novel** susceptibility genes (pqac-00000050) | Provides population-genetic evidence that altered RETREG2 expression may influence glioma susceptibility; translationally relevant as a candidate risk gene rather than a validated biomarker | Robinson et al., **Scientific Reports** (Jan 2021), doi:10.1038/s41598-021-82169-5, https://doi.org/10.1038/s41598-021-82169-5 (pqac-00000050) |
| **Tumor microenvironment relevance: exosomal miR-940 directly targets FAM134A** | Primary/translational | Exosomal miRNA profiling, human MSC osteogenic differentiation assays, in vivo bone metastasis model with miR-940–overexpressing cancer cells | hsa-miR-940 was enriched in osteoblastic phenotype–inducing prostate cancer exosomes; it directly targeted **FAM134A** and promoted osteogenic differentiation of human MSCs; miR-940–overexpressing MDA-MB-231 cells induced extensive osteoblastic lesions in vivo (quantitative values not provided in excerpt) (pqac-00000049) | Shows RETREG2 can be pathophysiologically regulated by tumor-secreted miRNA signals, linking it to osteoblastic bone metastasis biology and possible biomarker/therapeutic interest | Hashimoto et al., **PNAS** (Feb 2018), doi:10.1073/pnas.1717363115, https://doi.org/10.1073/pnas.1717363115 (pqac-00000049) |


*Table: This table compiles the strongest available evidence for human RETREG2/FAM134A, spanning core functional experiments, family-level mechanistic advances, in vivo paralogue studies, and translational disease links. It is useful as a compact evidence map showing what is directly demonstrated for RETREG2 versus what is inferred from the broader FAM134 family.*