Lysosomal targeting of autophagosomes by the TECPR domain of TECPR2

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3096-3108
Number of pages13
JournalAutophagy
Volume17
Issue number10
DOIs
StatePublished - 2021

Funding

FundersFunder number
Collaborative Research Center 1177BE 4685/7-1, 259130777
Joint NRF
Marie Skłodowska-Curie ETN
Sagol Longevity Foundation
Yeda-Sela Center for basic research
Horizon 2020 Framework Programme765912
Deutsche Forschungsgemeinschaft390857198
Israel Science Foundation215/19, 3221/19

    Keywords

    • Autophagy
    • SPG49
    • TECPR2
    • lysosome
    • neurodegeneration

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