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Lysosomal targeting of autophagosomes by the TECPR domain of TECPR2

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posted on 13.10.2021, 19:21 by Milana Fraiberg, Bat-Chen Tamim-Yecheskel, Kamilya Kokabi, Nemanja Subic, Gali Heimer, Franziska Eck, Karsten Nalbach, Christian Behrends, Bruria Ben-Zeev, Oren Shatz, Zvulun Elazar

TECPR2 (tectonin beta-propeller repeat containing 2) is a large, multi-domain protein comprised of an amino-terminal WD domain, a middle unstructured region and a carboxy-terminal TEPCR domain comprises of six TECPR repeats followed by a functional LIR motif. Human TECPR2 mutations are linked to spastic paraplegia type 49 (SPG49), a hereditary neurodegenerative disorder. Here we show that basal macroautophagic/autophagic flux is impaired in SPG49 patient fibroblasts in the form of accumulated autophagosomes. Ectopic expression of either full length TECPR2 or the TECPR domain rescued autophagy in patient fibroblasts in a LIR-dependent manner. Moreover, this domain is recruited to the cytosolic leaflet of autophagosomal and lysosomal membranes in a LIR- and VAMP8-dependent manner, respectively. These findings provide evidence for a new role of the TECPR domain in particular, and TECPR2 in general, in lysosomal targeting of autophagosomes via association with Atg8-family proteins on autophagosomes and VAMP8 on lysosomes.

Abbreviations: HOPS: homotypic fusion and vacuole protein sorting; LIR: LC3-interacting region; SPG49: spastic paraplegia type 49; STX17: syntaxin 17; TECPR2: tectonin beta-propeller repeat containing 2; VAMP8: vesicle associated membrane protein 8

Funding

Z.E. is the incumbent of the Harold Korda Chair of Biology. We are grateful for funding from the Israel Science Foundation (Grant #215/19), the Sagol Longevity Foundation, Joint NRF - ISF Research Fund (Grant #3221/19), and the Yeda-Sela Center for Basic Research. Z. E. and N.S. are supported by a Marie Skłodowska-Curie ETN grant under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No 765912 DRIVE). C.B. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the frameworks of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198), the Collaborative Research Center 1177 (ID 259130777) as well as the research grant BE 4685/7-1.

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