AP-1γ2 is an adaptor protein 1 variant required for endosome-to-Golgi trafficking of the mannose-6-P receptor (CI-MPR) and ATP7B copper transporter

Author(s)

Tavares, Lucas Alves ; Rodrigues, Roger Luiz ; da Costa, Cristina Santos ; Nascimento, Jonas Alburqueque ; de Carvalho, Julianne Vargas ; de Carvalho, Andreia Nogueira ; Mardones, Gonzalo A. ; daSilva, Luis L. P.

• Document type: Journal article
• Source: Journal of Biological Chemistry; v. 300, n. 3, p. 17-pg., 2024-03-01.

Abstract

Selective retrograde transport from endosomes back to the trans-Golgi network (TGN) is important for maintaining protein homeostasis, recycling receptors, and returning molecules that were transported to the wrong compartments. Two important transmembrane proteins directed to this pathway are the Cation-Independent Mannose-6-phosphate receptor (CI-MPR) and the ATP7B copper transporter. Among CI-MPR functions is the delivery of acid hydrolases to lysosomes, while ATP7B facilitates the transport of cytosolic copper ions into organelles or the extracellular space. Precise subcellular localization of CI-MPR and ATP7B is essential for the proper functioning of these proteins. This study shows that both CIMPR and ATP7B interact with a variant of the clathrin adaptor 1 (AP-1) complex that contains a specific isoform of the gamma-adaptin subunit called gamma 2. Through synchronized anterograde trafficking and cell-surface uptake assays, we demonstrated that AP-1 gamma 2 is dispensable for ATP7B and CI-MPR exit from the TGN while being critically required for ATP7B and CI-MPR retrieval from endosomes to the TGN. Moreover, AP1 gamma 2 depletion leads to the retention of endocytosed CI-MPR in endosomes enriched in retromer complex subunits. These data underscore the importance of AP-1 gamma 2 as a key component in the sorting and trafficking machinery of CI-MPR and ATP7B, highlighting its essential role in the transport of proteins from endosomes. (AU)

• FAPESP's process: 16/18207-9 - Characterization of protein trafficking pathways involved in lysosome biogenesis and function in human cells
• Grantee: Lucas Alves Tavares
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/15280-5 - Study of molecular mechanisms associated with the modulation of the signaling pathway stimulated by type I interferons (JAK/STAT) by HIV-1
• Grantee: Roger Luiz Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/01182-1 - The functional characterization of AP-1 in the endolysosomal system and its relationship with the assembly of HIV-1
• Grantee: Lucas Alves Tavares
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/26306-2 - Investigation into the differential roles of two variants of the adaptor protein 1 (AP-1) complex in protein trafficking
• Grantee: Lucas Alves Tavares
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 19/27725-1 - Study of the mechanisms by which HIV-1 Nef promotes viral infectivity neutralising host cell restriction factors
• Grantee: Cristina Santos da Costa
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)