The life cycle of type IV collagen

Type IV collagen is a large triple helical molecule that forms a covalently cross-linked network within basement membranes (BMs). Type IV collagen networks play key roles in mechanically supporting tissues, shaping organs, filtering blood, and cell signaling. To ensure tissue health and function, all aspects of the type IV collagen life cycle must be carried out accurately. However, the large triple helical structure and complex life-cycle of type IV collagen, poses many challenges to cells and tissues. Type IV collagen predominantly forms heterotrimers and to ensure proper construction, expression of the distinct α-chains that comprise a heterotrimer needs tight regulation. The α-chains must also be accurately modified by several enzymes, some of which are specific to collagens, to build and stabilize the triple helical trimer. In addition, type IV collagen is exceptionally long (400 nm) and thus the packaging and trafficking of the triple helical trimer from the ER to the Golgi must be modified to accommodate the large type IV collagen molecule. During ER-to-Golgi trafficking, as well as during secretion and transport in the extracellular space, type IV collagen also associates with specific chaperone molecules that maintain the structure and solubility of collagen IV. Type IV collagen trimers are then delivered to BMs from local and distant sources where they are integrated into BMs by interactions with cell surface receptors and many diverse BM resident proteins. Within BMs type IV collagen self-associates into a network and is crosslinked by BM resident enzymes. Finally, homeostatic type IV collagen levels in BMs are maintained by poorly understood mechanisms involving proteolysis and endocytosis. Here, we provide an overview of the life cycle of collagen IV, highlighting unique mechanisms and poorly understood aspects of type IV collagen regulation.