Annexins as organizers of cholesterol- and sphingomyelin-enriched membrane microdomains in Niemann-Pick type C disease

Abstract

Growing evidence suggests that membrane microdomains enriched in cholesterol and sphingomyelin are sites for numerous cellular processes, including signaling, vesicular transport, interaction with pathogens, and viral infection, etc. Recently some members of the annexin family of conserved calcium and membrane-binding proteins have been recognized as cholesterol-interacting molecules and suggested to play a role in the formation, stabilization, and dynamics of membrane microdomains to affect membrane lateral organization and to attract other proteins and signaling molecules onto their territory. Furthermore, annexins were implicated in the interactions between cytosolic and membrane molecules, in the turnover and storage of cholesterol and in various signaling pathways. In this review, we focus on the mechanisms of interaction of annexins with lipid microdomains and the role of annexins in membrane microdomains dynamics including possible participation of the domain-associated forms of annexins in the etiology of human lysosomal storage disease called Niemann-Pick type C disease, related to the abnormal storage of cholesterol in the lysosome-like intracellular compartment. The involvement of annexins and cholesterol/sphingomyelin-enriched membrane microdomains in other pathologies including cardiac dysfunctions, neurodegenerative diseases, obesity, diabetes mellitus, and cancer is likely, but is not supported by substantial experimental observations, and therefore awaits further clarification.

Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration

“…In early endosomes, the interplay of AnxA2 with cholesterol regulates biogenesis of multivesicular transport intermediates destined for LEs (53). In LEs, AnxA6 blocks the exit of cholesterol causing an NPC-like phenotype (14,54). AnxA6 appears to interfere with NPC function because NPC1 overexpression diminished LE cholesterol accumulation and restored trafficking and cellular distribution of caveolin-1 (14) and SNAP23/Stx4 (15).…”

Annexin A2 Heterotetramer: Structure and Function

“…However, while some annexins bind membranes in a calcium-independent manner, other annexins can insert into membranes as monomers or hexamers [8]. The annexins have also been shown to participate in a variety of membrane related functions such as exocytosis, endocytosis, the regulation of ion transport across membranes, membrane reorganization, vesicular trafficking and redox regulation (reviewed in [2,3,9]).…”

MiR-206 Controls the Phenotypic Modulation of Pulmonary Arterial Smooth Muscle Cells Induced by Serum from Rats with Hepatopulmonary Syndrome by Regulating the Target Gene, Annexin A2

“…The ability of ANXA2 to form a heterotetrameric complex plays a key role in Ca 2+ -dependent exocytosis, endocytosis and membrane organisation [4,5,6]. Previous studies have indicated that ANXA2 is an important regulatory protein in the process of proliferation, migration, skeletal formation and angiogenesis in a variety of malignant tumours, such as liver cancer, pancreatic cancer, breast cancer and lung cancer [7,8,9].…”