TANGO1 builds a machine for collagen export by recruiting and spatially organizing COPII, tethers and membranes

Abstract

Collagen export from the endoplasmic reticulum (ER) requires TANGO1, COPII coats, and retrograde fusion of ERGIC membranes. How do these components come together to produce a transport carrier commensurate with the bulky cargo collagen? TANGO1 is known to form a ring that corrals COPII coats, and we show here how this ring or fence is assembled. Our data reveal that a TANGO1 ring is organized by its radial interaction with COPII, and lateral interactions with cTAGE5, TANGO1-short or itself. Of particular interest is the finding that TANGO1 recruits ERGIC membranes for collagen export via the NRZ (NBAS/RINT1/ZW10) tether complex. Therefore, TANGO1 couples retrograde membrane flow to anterograde cargo transport. Without the NRZ complex, the TANGO1 ring does not assemble, suggesting its role in nucleating or stabilising this process. Thus, coordinated capture of COPII coats, cTAGE5, TANGO1-short, and tethers by TANGO1 assembles a collagen export machine at the ER.

A physical mechanism of TANGO1-mediated bulky cargo export

“…izes with proteins of the TANGO1 family (such as TANGO1 itself, the TANGO1-like protein 59 cTAGE5, and the spliced isoform TANGO1-Short) (Saito et al, 2011;Maeda, Saito and 60 Katada, 2016; Raote et al, 2018). Recently, we visualized procollagen export domains with 61 high lateral spatial resolution using stimulated emission depletion (STED) nanoscopy in mam-62 malian tissue cultured cells (Raote et al, 2017.…”

“…In such a situa-611 tion, carrier expansion -according to the results of our model-can proceed via three different 612 scenarios: (i) increase in the binding affinity of COPII coats to the membrane (Figure 5C and 613 Figure 6); (ii) appearance of a directed force applied at the growing carrier and pointing to-614 wards the cytosol (Figure 5D and Figure 6); and (iii) local reduction of the membrane tension 615 (Figure 6). TANGO1 can directly or indirectly control each of these possibilities (Ma and 616 Goldberg, 2016; Raote et al, 2018). Interestingly, the TANGO1 ring properties, such as the 617 linactant power of TANGO1 or the TANGO1 filament bending rigidity, are not drivers of the 618 incomplete bud to long transport intermediate transition (Figure 6C,D), but they seem to act 619 more as kinetic controllers of the transition by preventing bud closure (Figure 4).…”

Broadly Conserved TMEM-131 Family Proteins in Collagen Production and Secretory Cargo Trafficking

“…HSP47 is a collagen-specific chaperone that recognizes collagen trimers in the ER and prevents their premature aggregation during secretion (48). Collagen secretion also requires TANGO1, a protein that facilitates the assembly of a collagen export machine in the ER (19,20). However, no apparent HSP47 and TANGO1 orthologs can be found in C. elegans or Drosophila (21-23).…”

“…TRAPPC8 is a key component of TRAPP III, a subtype of TRAPP that acts as a guanine nucleotide exchange factor (GEF) to activate Rab GTPase to promote ER-to-Golgi cargo trafficking. Collagen production also requires HSP47, a procollagen chaperone in the ER, and TANGO1, an ER transmembrane protein that facilitates the export of bulky cargo with collagen (19,20).Intriguingly, HSP47 and TANGO1 orthologs are present only in vertebrates (21-23), raising the question whether mechanisms conserved in all animals exist to recognize procollagens for assembly into export-competent collagen trimers in route for secretion.In this study, we identify a previously uncharacterized C. elegans gene tmem-131 that defines an evolutionarily conserved protein family important for procollagen recruitment and secretion. The exoskeleton of C. elegans, is a complex collagen matrix that comprises many distinct mature collagen proteins, including COL-19, an adult-specific, hypodermally synthesized collagen (24).…”

“…TRAPPC8 is a key component of TRAPP III, a subtype of TRAPP that acts as a guanine nucleotide exchange factor (GEF) to activate Rab GTPase to promote ER-to-Golgi cargo trafficking. Collagen production also requires HSP47, a procollagen chaperone in the ER, and TANGO1, an ER transmembrane protein that facilitates the export of bulky cargo with collagen (19,20).…”