{"doi":"10.1101/2020.02.22.944264","title":"ALG-2 and Peflin Stimulate or Inffibit Copii Targeting and Secretion in Response to Calcium Signaling","abstract":"ABSTRACT ER-to-Golgi transport is the first step in the constitutive secretory pathway which, unlike regulated secretion, is believed to proceed non-stop regardless of Ca 2+ flux. Rowever, here we demonstrate that penta-EF hand (PEF) proteins ALG-2 and peflin constitute a hetero-bifunctional COPII regulator that responds to Ca 2+ signaling by adjusting the ER export rate of COPII-sorted cargos up or down by ~50%. At steady-state Ca 2+ , ALG-2/peflin hetero-complexes bind to ER exit sites (ERES) through the ALG-2 subunit to confer a low, buffered secretion rate, while peflin-lacking ALG-2 complexes markedly stimulate secretion. During Ca 2+ signaling, ALG-2 complexes lacking peflin can either increase or decrease the secretion rate depending on signaling intensity and duration-phenomena that could contribute to cellular growth and intercellular communication, following secretory increases, or protection from excitotoxicity and infection following decreases. In epithelial normal rat kidney (NRK) cells, the Ca 2+ -mobilizing agonist ATP causes ALG-2 to depress ER export, while in neuroendocrine PC12 cells, Ca 2+ mobilization by ATP results in ALG-2-dependent enhancement of secretion. Within the NRK cell model, distinct Ca 2+ signaling patterns can produce opposing ALG-2-dependent effects on secretion. Mechanistically, ALG-2-dependent depression of secretion involves decreased COPTT outer shell and increased peflin targeting to ERES, while ALG-2-dependent enhancement of secretion involves increased COPTT outer shell and decreased peflin at ERES. PEF protein complexes represent a true regulator of transport as they are dispensable for secretion yet adjust the secretion rate to physiological conditions. Their dynamics affects secretion of important physiological cargoes such as collagen T and significantly impacts ER stress.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127955,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":577666,"name":"Danette Kowal Seiler","orcid":"0000-0003-4038-8225","position":1,"is_corresponding":false},{"id":279756,"name":"Tucker Costain","orcid":null,"position":2,"is_corresponding":false},{"id":577667,"name":"Corina T. Madreiter‐Sokolowski","orcid":"0000-0002-8631-9949","position":3,"is_corresponding":false},{"id":103626,"name":"David E. Gordon","orcid":"0000-0001-7954-0306","position":4,"is_corresponding":false},{"id":575698,"name":"Andrew A. Peden","orcid":"0000-0003-0144-7712","position":5,"is_corresponding":false},{"id":144282,"name":"Roland Malli","orcid":"0000-0001-6327-8729","position":6,"is_corresponding":false},{"id":274039,"name":"Wolfgang F. Graier","orcid":"0000-0003-1871-3298","position":7,"is_corresponding":false},{"id":578216,"name":"Jesse C. Ray","orcid":null,"position":8,"is_corresponding":false},{"id":578215,"name":"John Sargeant","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-18T23:15:34.966380Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}