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@ARTICLE{Shi:300185,
author = {H. Shi and Y. Yang and J. Gao and S. Kumar and H. Xie and
Z. Chen and J. Lyu and H. Sihto and V. Koljonen and S.
Vega-Rubin-de-Celis and V. Vukojevic and F. Farnebo and V.
Björnhagen and A. Höög and C. C. Juhlin and L. Lee and M.
Wickström and J. C. Becker$^*$ and J. I. Johnsen and C.
Larsson and W.-O. Lui},
title = {{K}it-mediated autophagy suppression driven by a viral
oncoprotein emerges as a crucial survival mechanism in
{M}erkel cell carcinoma.},
journal = {Autophagy},
volume = {21},
number = {7},
issn = {1554-8627},
address = {Abingdon, Oxon},
publisher = {Taylor $\&$ Francis},
reportid = {DKFZ-2025-00662},
pages = {1523-1543},
year = {2025},
note = {ISSN 1554-8635 / 2025 Jul;21(7):1523-1543},
abstract = {The KIT/c-KIT proto-oncogene is frequently over-expressed
in Merkel cell carcinoma (MCC), an aggressive skin cancer
commonly caused by Merkel cell polyomavirus (MCPyV). Here,
we demonstrated that truncated MCPyV-encoded large T-antigen
(LT) suppressed macroautophagy/autophagy by stabilizing and
sequestering KIT in the paranuclear compartment via binding
VPS39. KIT engaged with phosphorylated BECN1, thereby
enhancing its association with BCL2 while diminishing its
interaction with the PIK3C3 complex. This process ultimately
resulted in the suppression of autophagy. Depletion of KIT
triggered both autophagy and apoptosis, and decreased LT
expression. Conversely, blocking autophagy in KIT-depleted
cells restored LT levels and rescued apoptosis.
Additionally, stimulating autophagy efficiently increased
cell death and inhibited tumor growth of MCC xenografts in
mice. These insights into the interplay between MCPyV LT and
autophagy regulation reveal important mechanisms by which
viral oncoproteins are essential for MCC cell viability.
Thus, autophagy-inducing agents represent a therapeutic
strategy in advanced MCPyV-associated MCC.Abbreviation:
3-MA, 3-methyladenine; AL, autolysosome; AP, autophagosome;
Baf-A1, bafilomycin A1; BARA, β-α repeated autophagy
specific domain; BH3, BCL2 homology 3 domain; CCD,
coiled-coil domain; CHX, cycloheximide; Co-IP,
co-immunoprecipitation; CQ, chloroquine; CTR, control; DAPI,
4',6-diamidino-2-phenylindole; EBSS, Earle's balanced salt
solution; ECD, evolutionarily conserved domain; EEE,
three-tyrosine phosphomimetic mutations Y229E Y233E Y352E;
ER, endoplasmic reticulum; FFF, three-tyrosine
non-phosphomimetic mutations; FFPE, formalin-fixed
paraffin-embedded; FL, full-length; GIST, gastrointestinal
stromal tumor; IB, immunoblotting; IHC,
immunohistochemistry; KIT-HEK293, KIT stably expressing
HEK293 cells; KRT20/CK20, keratin 20; LT, large T-antigen;
LT339, MCPyV truncated LT antigen; LTco, codon-optimized
MCPyV LT antigen; MCC, Merkel cell carcinoma; MCPyV-,
MCPyV-negative; MCPyV, Merkel cell polyomavirus; MCPyV+,
MCPyV-positive; PARP1, poly(ADP-ribose) polymerase 1; PCI,
pan-caspase inhibitor; PI, propidium iodide; PtdIns3K, class
III phosphatidylinositol 3-kinase; PtdIns3P,
phosphatidylinositol-3-phosphate; RB1, RB transcriptional
corepressor 1; RTKs, receptor tyrosine kinases; KITLG/SCF,
KIT ligand; sT, small T-antigen; sTco, codon-optimized MCPyV
sT antigen; T-B, Tat-BECN1; T-S, Tat-scrambled; TEM,
transmission electron microscopy.},
keywords = {Autophagy (Other) / BECN1 (Other) / KIT (Other) / Merkel
cell carcinoma (Other) / Merkel cell polyomavirus (Other) /
large T antigen (Other)},
cin = {ED01},
ddc = {570},
cid = {I:(DE-He78)ED01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40108758},
doi = {10.1080/15548627.2025.2477385},
url = {https://inrepo02.dkfz.de/record/300185},
}