TBC1D20 mediates autophagy as a key regulator of autophagosome maturation. Autophagy 2016 Oct 02;12(10):1759-1775
Date
08/04/2016Pubmed ID
27487390Pubmed Central ID
PMC5079675DOI
10.1080/15548627.2016.1199300Scopus ID
2-s2.0-84980378961 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
In humans, loss of TBC1D20 (TBC1 domain family, member 20) protein function causes Warburg Micro syndrome 4 (WARBM4), an autosomal recessive disorder characterized by congenital eye, brain, and genital abnormalities. TBC1D20-deficient mice exhibit ocular abnormalities and male infertility. TBC1D20 is a ubiquitously expressed member of the family of GTPase-activating proteins (GAPs) that increase the intrinsically slow GTP-hydrolysis rate of small RAB-GTPases when bound to GTP. Biochemical studies have established TBC1D20 as a GAP for RAB1B and RAB2A. However, the cellular role of TBC1D20 still remains elusive, and there is little information about how the functional loss of TBC1D20 causes clinical manifestations in WARBM4-affected children. Here we evaluate the role of TBC1D20 in cells carrying a null mutant allele, as well as TBC1D20-deficient mice, which display eye and testicular abnormalities. We demonstrate that TBC1D20, via its RAB1B GAP function, is a key regulator of autophagosome maturation, a process required for maintenance of autophagic flux and degradation of autophagic cargo. Our results provide evidence that TBC1D20-mediated autophagosome maturation maintains lens transparency by mediating the removal of damaged proteins and organelles from lens fiber cells. Additionally, our results show that in the testes TBC1D20-mediated maturation of autophagosomes is required for autophagic flux, but is also required for the formation of acrosomes. Furthermore TBC1D20-deficient mice, while not mimicking severe developmental brain abnormalities identified in WARBM4 affected children, display disrupted neuronal autophagic flux resulting in adult-onset motor dysfunction. In summary, we show that TBC1D20 has an essential role in the maturation of autophagosomes and a defect in TBC1D20 function results in eye, testicular, and neuronal abnormalities in mice implicating disrupted autophagy as a mechanism that contributes to WARBM4 pathogenesis.
Author List
Sidjanin DJ, Park AK, Ronchetti A, Martins J, Jackson WTAuthor
Danielle Sidjanin Maier PhD, MSN APP Supervisor Inpatient 2 in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcrosomeAnimals
Autophagosomes
Autophagy
Cataract
Embryo, Mammalian
Fibroblasts
Lens, Crystalline
Male
Mice
Models, Biological
Motor Activity
Testis
Ubiquitination
rab1 GTP-Binding Proteins
