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. 2020 Feb 10;133(3):jcs235044. doi: 10.1242/jcs.235044

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© 2020. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Fig. 7. — Sequence determinants of GDE2 trafficking and biological activity. (A) The C-terminal region (aa 530–550 or 541–550) is essential for proper expression, secretion and membrane insertion. The sequence from aa 551–560 determines endocytosis (with a key role for residue Leu-553, indicated by an arrowhead) and Rab4 fast recycling preference, but negatively regulates GDE2 function. Sequence from aa 561–570 is required for proper GDE2 recycling and function. Residues in white are not conserved between mammalian, chicken and/or zebrafish GDE2 (cf. Fig. 2A). (B) Scheme of membrane trafficking, localization and biological output of GDE2 and the indicated truncation mutants, acting in a cell-autonomous manner through GPC6 cleavage and an as-yet-unknown transmembrane effector. GDE2 is constitutively internalized while the majority of endocytosed GDE2 recycles along Rab4⁺ and Rab11⁺ routes in a sequence-dependent manner. A small percentage of internalized GDE2 is sorted to Rab7⁺ late endosomes and lysosomes (not illustrated). GDE2(ΔC570) shows wild-type trafficking behavior and GPC6-releasing activity, yet is not fully signaling competent. GDE2(ΔC560) shows preference for Rab4-driven fast recycling and is dysfunctional, whereas GDE2(ΔC550) is retained at the cell surface with regain of function. The endocytosis regulatory residue Leu-553 is indicated by a black arrowhead. Signaling efficacy is inferred from GPC6 shedding and induction of neuronal differentiation marker genes. See text for further details.