Overlapping Machinery in Lysosome-Related Organelle Trafficking: A Lesson from Rare Multisystem Disorders

Cells. 2022 Nov 21;11(22):3702. doi: 10.3390/cells11223702.


Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.

Keywords: Arthrogryposis-Renal dysfunction-Cholestasis; Griscelli syndrome; Hermansky–Pudlak Syndrome; VIPAR; VPS33B; cargo-sorting; endosomes; lysosome-related organelles; membrane trafficking; multisystem disorders.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthrogryposis*
  • Cholestasis* / metabolism
  • Humans
  • Kidney Diseases* / metabolism
  • Lysosomes / metabolism
  • Melanosomes / metabolism
  • Rare Diseases / metabolism

Grants and funding

F.S. and B.B acknowledge funding from the National Health and Medical Research Council Ideas Grant APP2001396 and Philanthropic funding from Princess Alexandra Hospital Research Fund and Aveo communities.