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9.B.113 The Collagen Secretory Protein, Mia3 (Mia3) Family

Melanoma inhibitory activity member 3 (MIA3/TANGO1) is an evolutionarily conserved endoplasmic reticulum resident transmembrane protein. In vitro studies have shown that it is required for the loading of collagen VII into COPII-coated transport vesicles. Wilson et al. (2011) showed that mice lacking Mia3 are defective for the secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX. Collagen deposition by these cell types is abnormal, and the extracellular matrix composition is compromised. These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton. Chondrocyte maturation and bone mineralization are severely compromised in Mia3-null embryos, leading to dwarfism and neonatal lethality. Thus, Mia3 may be required for the efficient secretion of all collagens in higher organisms (Wilson et al., 2011).

Secretory proteins are exported from special domains of the endoplasmic reticulum (ER) termed ER exit sites, via COPII-coated carriers. Maeda et al. 2019 showed that TANGO1 and Sec16 cooperatively organize mammalian ER exit sites for efficient secretion. Domains are abundant in transmembrane complexes (TANGO1/cTAGE5/Sec12 = 9.B.113.1.1/9.B.113.1.4/Q9HCU5 with 417 aas and 3 TMSs, one N-terminal and two close together further on) juxtaposed to Sec16A (O15027). This domain can be distinguished from the inner and the outer coats of COPII proteins within each mammalian ER exit site. Cargoes are partially concentrated in the domain for secretion. These observations suggest that mammalian ER exit sites compartmentalize proteins according to their function in COPII vesicle formation (Maeda et al. 2019). Sec23A (Q15436, 765 aas) may be a component of athe coat protein complex II (COPII).

TANGO1 organizes membranes at the interface of the endoplasmic reticulum (ER) and ERGIC/Golgi. It corrals retrograde membranes at ER exit sites to create an export conduit. The retrograde membrane is, in itself, an anterograde carrier (Raote et al. 2020). This mode of forward transport necessitates a mechanism to prevent membrane mixing between the ER and the retrograde membrane. TANGO1 has an unusual membrane helix organisation, composed of one membrane-spanning helix (TM) and another that penetrates the inner leaflet (IM). Raote et al. 2020 reconstituted these membrane helices in model membranes and showed that TM and IM together reduce the flow of lipids at a region of defined shape. They also found that the helices align TANGO1 around an ER exit site. Possibly this is a mechanism to prevent membrane mixing during TANGO1-mediated transfer of bulky secretory cargos from the ER to the ERGIC/Golgi via a tunnel.


References associated with 9.B.113 family:

Bard, F., L. Casano, A. Mallabiabarrena, E. Wallace, K. Saito, H. Kitayama, G. Guizzunti, Y. Hu, F. Wendler, R. Dasgupta, N. Perrimon, and V. Malhotra. (2006). Functional genomics reveals genes involved in protein secretion and Golgi organization. Nature 439: 604-607. 16452979
Elliott, L., I. Moore, and C. Kirchhelle. (2020). Spatio-temporal control of post-Golgi exocytic trafficking in plants. J Cell Sci 133:. 32102937
Ishikawa, Y., S. Ito, K. Nagata, L.Y. Sakai, and H.P. Bächinger. (2016). Intracellular mechanisms of molecular recognition and sorting for transport of large extracellular matrix molecules. Proc. Natl. Acad. Sci. USA 113: E6036-E6044. 27679847
Lekszas, C., O. Foresti, I. Raote, D. Liedtke, E.M. König, I. Nanda, B. Vona, P. De Coster, R. Cauwels, V. Malhotra, and T. Haaf. (2020). Biallelic mutations cause a novel syndromal disease due to hampered cellular collagen secretion. Elife 9:. 32101163
Lerner, D.W., D. McCoy, A.J. Isabella, A.P. Mahowald, G.F. Gerlach, T.A. Chaudhry, and S. Horne-Badovinac. (2013). A Rab10-dependent mechanism for polarized basement membrane secretion during organ morphogenesis. Dev Cell 24: 159-168. 23369713
Maeda, M., K. Kurokawa, T. Katada, A. Nakano, and K. Saito. (2019). COPII proteins exhibit distinct subdomains within each ER exit site for executing their functions. Sci Rep 9: 7346. 31089171
Raote, I., A.M. Ernst, F. Campelo, J.E. Rothman, F. Pincet, and V. Malhotra. (2020). TANGO1 membrane helices create a lipid diffusion barrier at curved membranes. Elife 9:. 32452385
Saito, K. and M. Maeda. (2019). Not just a cargo receptor for large cargoes; an emerging role of TANGO1 as an organizer of ER exit sites. J Biochem 166: 115-119. 31098622
Santos, A.J., C. Nogueira, M. Ortega-Bellido, and V. Malhotra. (2016). TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum. J. Cell Biol. 213: 343-354. 27138255
Wilson, D.G., K. Phamluong, L. Li, M. Sun, T.C. Cao, P.S. Liu, Z. Modrusan, W.N. Sandoval, L. Rangell, R.A. Carano, A.S. Peterson, and M.J. Solloway. (2011). Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse. J. Cell Biol. 193: 935-951. 21606205