Tales of the ER-Golgi Frontier: Drosophila-Centric Considerations on Tango1 Function

Abstract

In the secretory pathway, the transfer of cargo from the ER to the Golgi involves dozens of proteins that localize at specific regions of the ER called ER exit sites (ERES), where cargos are concentrated preceding vesicular transport to the Golgi. Despite many years of research, we are missing crucial details of how this highly dynamic ER-Golgi interface is defined, maintained and functions. Mechanisms allowing secretion of large cargos such as the very abundant collagens are also poorly understood. In this context, Tango1, discovered in the fruit fly Drosophila and widely conserved in animal evolution, has received a lot of attention in recent years. Tango1, an ERES-localized transmembrane protein, is the single fly member of the MIA/cTAGE family, consisting in humans of TANGO1 and at least 14 different related proteins. After its discovery in flies, a specific role of human TANGO1 in mediating secretion of collagens was reported. However, multiple studies in Drosophila have demonstrated that Tango1 is required for secretion of all cargos. At all ERES, through self-interaction and interactions with other proteins, Tango1 aids ERES maintenance and tethering of post-ER membranes. In this review, we discuss discoveries on Drosophila Tango1 and put them in relation with research on human MIA/cTAGE proteins. In doing so, we aim to offer an integrated view of Tango1 function and the nature of ER-Golgi transport from an evolutionary perspective.

Keywords: COPII; ER exit site; collagen; extracellular matrix; secretion; traffic.

FIGURE 1

Schematic representation of Drosophila Tango1 and proteins of the MIA/cTAGE family, found exclusively in animals. A single representative is found in flies, consisting of an ER-lumenal part, displaying a highly conserved SH3 domain, and a cytoplasmic part, containing coiled coils and a C-terminal proline-rich region. In the sponge Amphimedon queenslandica, a representative of the phylum Porifera, the most basal metazoans, ER lumenal and cytoplasmic parts are found as separate proteins. In the sea anemone Nematostella vectensis, a cnidarian, a complete TANGO1 protein is found. Human MIA/cTAGE family members include TANGO1 and TANGO1-like (TALI) as complete proteins, but also ER-lumenal and transmembrane cytoplasmic forms, and also at least one predicted completely cytoplasmic CTAGE5 isoform (CTAGE5 cyt). Sequences represented and corresponding RefSeq accession numbers are: Dmel Tango1 (NP_609058.2), Aque NST1-like (XP_019849291.1), Aque CTAGE5-like (XP_019849290.1), Nvec TANGO1 (XP_032221684.1), Hsap TANGO1 (NP_940953.2), Hsap_MIA3 (XP_937620.1), Hsap_TANGO1S (NP_001287796.1), Hsap TALI (NP_001316143.1), Hsap MIA2 (NP_473365.3), Hsap CTAGE5 (NP_976231.1), Hsap CTAGE5cyt (XP_011535087.1), Hsap MIA (NP_001189482.1), Hsap OTOR (NP_064542.1), Hsap CTAGE2 (NP_758441.2), Hsap CTAGE4 (NP_940897.2), Hsap CTAGE6 (NP_848656.2), Hsap CTAGE8 (NP_001265436.1), Hsap CTAGE9 (NP_001139131.1), and Hsap CTAGE15 (NP_001008747.1).

FIGURE 2

(A) Schematic representation of Drosophila Tango1. (B) Superresolution micrograph (3D-SIM) showing the localization of Tango1 (antibody staining) at ER exit sites (ERES) in a Drosophila fat body cell. RFP.Rab1 and cis-Golgi marker GM130 are shown as well. (C) Tango1 preserves ERES size and connection ERES-Golgi. Tango1 knock-down (Tango1ⁱ) causes decrease in the size of ERES, marked with Sec16.GFP, and their uncoupling from Golgi (cis-Golgi marker GM130). (D) Role of Drosophila Tango1 in defining ERES, tethering Golgi membranes and stabilizing the ER-Golgi interface at ERES-Golgi units. Interactions with itself, Grasp65, GM130, Rab1 and Sar1 have been documented (Liu et al., 2017). Additionally, human TANGO1 and other MIA/cTAGE proteins have been collectively found to interact with multiple ERES proteins and ER-Golgi traffic regulators.