Systematic Annotation of Secretory Pathway Genes As a Discovery Tool for New Therapeutic Targets in AL Amyloidosis

Background: FLC secretion drives pathogenesis in AL amyloidosis yet molecular mechanisms underlying the protein network supporting FLC secretion are uncharacterised and therapeutic strategies targeting them do not exist. Recently, The Protesotasis Consortium (Elsasser et al.) published a comprehensive annotation of the Human Proteostasis Network; however, genes involved in the vesicular transport system from transgolgi to cell membrane (terminal secretory pathway) were not included. We were interested in systematically annotating these genes to support therapeutic discoveries in AL amyloidosis and other secretory disorders.

Methods: Genes involved in the plasma cell secretory pathway were identified by two criteria: ‘entity-based’ and ‘domain-based’. ‘Entity-based’ inclusion involved genes previously annotated in literature to be involved in the secretory pathway. ‘Domain-based’ inclusion encompassed genes containing structural domains and motifs enriched in the secretory pathway. Twelve motifs were identified: AAA, Arf, C2/Mun, SNARE, NSR, Proppin, Ras, Rhomboid, Rint, SM, SNAP, ZW10; from which novel genes were incorporated.

Results: Using the approach above, we compiled a list of 1262 putative genes involved in the secretory pathway. Entity-based inclusions encompassed 1,087 genes while domain inclusion supplemented 175 genes. We organized these genes based on subcellular localization and function. We detailed 8 localization categories and 13 function categories. We constructed a map combining these 2 variables to obtain a tentative model of the terminal secretory pathway.

Conclusion: This is the first systematic effort to compile a comprehensive, task-oriented annotation of the terminal secretory pathway with the overarching goal to support basic and translational research efforts. Seen through the lens of AL amyloidosis research, this tool will be useful to develop novel treatments targeting light chain secretion to improve outcome for patients.

Bianchi:Prothena: Consultancy.