New components of mucin secretion
- External Seminar
- miércoles, 17 febrero 21
Gerard Cantero-Recasens, PhD
Renal Physiopathology group Vall d'Hebron Research Institute
Title: New components of mucin secretion
Mucins are the major macro-components of the mucus layer that protects our epithelium from toxins, pathogens and allergens, contributing to the innate defensive system. Mucins are secreted by specialized goblet cells that line the mucosal surfaces and limit the interactions between luminal insults and epithelium, thus regulating immune and inflammatory responses. Not surprising then, dysregulation of mucin secretion (responsible of the rheological properties of the mucus) by goblet cells is a hallmark of several pathologies (e.g. asthma and colorectal cancer). Nevertheless, how such a big cargoes can be transported from the ER to the Golgi, then packed in secretory vesicles and finally secreted after the appropriate stimuli remained poorly understood.
Our genetic screen to identify new components for this process revealed new mechanisms for secretion and sorting of mucins. First, I have described a new model for mucin secretion in which extracellular calcium entry is necessary for stimulated secretion (agonist-dependent), whereas intracellular calcium oscillations are required for baseline secretion (independent of external agonists). My data reveal that cooperation between the sodium channels TRPM4-TRPM5 and sodium-calcium exchangers (NCXs) promote the entry of extracellular Ca2+ to release mucin from goblet cells after stimulation (Cantero-Recasens et al, 2019). Baseline secretion, on the other hand, is triggered by intracellular calcium oscillations mostly by the function of ER-located ryanodine receptors (RYRs). These calcium oscillations act via a Ca2+ binding protein, KChIP3, to control the exocytosis of mucin granules (Cantero-Recasens et al, 2018; Cantero-Recasens et al, 2020). Altogether, I suggest KChIP3 is a high affinity Ca2+ sensor specific for baseline mucin secretion and acts as a break- a negative regulator- of fusion of mucin granules to plasma membrane. Second, my group is starting to identify the molecular identities and signals necessary for the sorting of mucins in different granules to be secreted depending on the organism requirements. In conclusion, my data propose the existence of chemically distinct pools of mucin granules for baseline and stimulated mucin secretion for different mucins and the ability to control the release propensity of these granules provides novel means to control dysregulated mucin secretion dependent pathologies of airway and the colon.
1: Cantero-Recasens G*, Burballa C, Duran M, Brouwers N, Malhotra V*. Palmitoylation of KChIP3 controls baseline mucin secretion. *Co-corresponding authors. bioRxiv. BIORXIV/2020/422936. doi.org/10.1101/2020.12.15.422936.
2: Cantero-Recasens G, Butnaru CM, Brouwers N, Mitrovic S, Valverde MA, Malhotra V. Sodium channel TRPM4 and sodium/calcium exchangers (NCX) cooperate in the control of Ca(2+)-induced mucin secretion from goblet cells. J Biol Chem. 2019 Jan 18;294(3):816-826. doi: 10.1074/jbc.RA117.000848. Epub 2018 Nov 27. PubMed PMID: 30482841; PubMed Central PMCID: PMC6341386.
3: Cantero-Recasens G, Butnaru CM, Valverde MA, Naranjo JR, Brouwers N, Malhotra V. KChIP3 coupled to Ca(2+) oscillations exerts a tonic brake on baseline mucin release in the colon. Elife. 2018 Oct 1;7. pii: e39729. doi: 10.7554/eLife.39729. PubMed PMID: 30272559; PubMed Central PMCID: PMC6167051.
4: Mitrovic S, Nogueira C, Cantero-Recasens G, Kiefer K, Fernández-Fernández JM, Popoff JF, Casano L, Bard FA, Gomez R, Valverde MA, Malhotra V. TRPM5-mediated calcium uptake regulates mucin secretion from human colon goblet cells. Elife. 2013 May 28;2:e00658. doi: 10.7554/eLife.00658. PubMed PMID: 23741618; PubMed Central PMCID: PMC3667631.