In vivo Insight into the Function of the Lysosomal Transmembrane Protein 55B (TMEM55B)

TMEM55B is a lysosomal membrane protein with relatively unknown functions in vivo. While TMEM55B was initially described as a phosphatidylinositol-4,5-bisphosphate-4-phosphatase, the protein has now been linked to other processes. By binding to the scaffold protein JIP4, TMEM55B mediates the transport of lysosomes in the retrograde direction along the microtubules using the motor protein complex dynein/dynactin.
I this study, the physiological role of TMEM55B-mediated lysosomal transport was investigated. It could be revealed that a TMEM55B deficiency in mice resulted in morphological changes within the seminiferous epithelium of the testis and the morphology of spermatozoa, leading to subfertility in male mice.

In order to investigate TMEM55Bs role more in depth interactome studies were conducted, identifying the GTPase-activating protein GBF1 and the guanosine triphosphate exchange factor TBC1D9B as potential new interaction partners for TMEM55. These two proteins could mediate TMEM55Bs binding to the scaffold protein JIP4 and thereby regulate for how long the complex stays attached to the motor protein.
Analysis of a double deficiency of TMEM55B and TMEM106B revealed, that there are multiple proteins able to mediate lysosomal transport in neurons. It was indicated that loss of a single protein might not severely impact neuron survivability, while the impairment of multiple retrograde transport pathways increases neurodegeneration. It may be assumed, that in neurodegenerative diseases with lysosomal accumulation phenotypes such as for example Alzheimer's Disease more than one trafficking pathway is disturbed.
Lastly, multiple results in this study present evidence, that the paralogue protein of TMEM55B, TMEM55A, fulfils redundant or additive functions in vivo in mice contradicting to so far published data.


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