TY - JOUR
T1 - Orthodenticle homeobox 2 is transported to lysosomes by nuclear budding vesicles
AU - Park, Jun Woo
AU - Lee, Eun Jung
AU - Moon, Eunyoung
AU - Kim, Hong Lim
AU - Kim, In Beom
AU - Hodzic, Didier
AU - Kim, Namsuk
AU - Kweon, Hee Seok
AU - Kim, Jin Woo
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Transcription factors (TFs) are transported from the cytoplasm to the nucleus and disappear from the nucleus after they regulate gene expression. Here, we discover an unconventional nuclear export of the TF, orthodenticle homeobox 2 (OTX2), in nuclear budding vesicles, which transport OTX2 to the lysosome. We further find that torsin1a (Tor1a) is responsible for scission of the inner nuclear vesicle, which captures OTX2 using the LINC complex. Consistent with this, in cells expressing an ATPase-inactive Tor1aΔE mutant and the LINC (linker of nucleoskeleton and cytoskeleton) breaker KASH2, OTX2 accumulated and formed aggregates in the nucleus. Consequently, in the mice expressing Tor1aΔE and KASH2, OTX2 could not be secreted from the choroid plexus for transfer to the visual cortex, leading to failed development of parvalbumin neurons and reduced visual acuity. Together, our results suggest that unconventional nuclear egress and secretion of OTX2 are necessary not only to induce functional changes in recipient cells but also to prevent aggregation in donor cells.
AB - Transcription factors (TFs) are transported from the cytoplasm to the nucleus and disappear from the nucleus after they regulate gene expression. Here, we discover an unconventional nuclear export of the TF, orthodenticle homeobox 2 (OTX2), in nuclear budding vesicles, which transport OTX2 to the lysosome. We further find that torsin1a (Tor1a) is responsible for scission of the inner nuclear vesicle, which captures OTX2 using the LINC complex. Consistent with this, in cells expressing an ATPase-inactive Tor1aΔE mutant and the LINC (linker of nucleoskeleton and cytoskeleton) breaker KASH2, OTX2 accumulated and formed aggregates in the nucleus. Consequently, in the mice expressing Tor1aΔE and KASH2, OTX2 could not be secreted from the choroid plexus for transfer to the visual cortex, leading to failed development of parvalbumin neurons and reduced visual acuity. Together, our results suggest that unconventional nuclear egress and secretion of OTX2 are necessary not only to induce functional changes in recipient cells but also to prevent aggregation in donor cells.
UR - http://www.scopus.com/inward/record.url?scp=85148974476&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36697-5
DO - 10.1038/s41467-023-36697-5
M3 - Article
C2 - 36849521
AN - SCOPUS:85148974476
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1111
ER -