Science - USA (2021-12-10)

RESEARCH ARTICLE SUMMARY

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CELL BIOLOGY

PI(3,4)P2-mediated cytokinetic abscission prevents

early senescence and cataract formation

Federico Gulluni, Lorenzo Prever, Huayi Li, Petra Krafcikova, Ilaria Corrado, Wen-Ting Lo,
Jean Piero Margaria, Anlu Chen, Maria Chiara De Santis, Sophie J. Cnudde, Joseph Fogerty,
Alex Yuan, Alberto Massarotti, Nasrin Torabi Sarijalo, Oscar Vadas, Roger L. Williams, Marcus Thelen,
David R. Powell, Markus Schueler, Michael S. Wiesener, Tamas Balla, Hagit N. Baris, Dov Tiosano,
Brian M. McDermott Jr., Brian D. Perkins, Alessandra Ghigo, Miriam Martini, Volker Haucke,
Evzen Boura, Giorgio Roberto Merlo, David A. Buchner, Emilio Hirsch

INTRODUCTION:In response to aging, senes-
cence plays a major role in the onset of various
degenerative diseases, including the slow de-
velopment of cataracts, a clouding of the eye
lens that troubles the vision of millions of peo-
ple worldwide. Transparent cells that form the
eye lens divide throughout lifetime, but in the
elderly, this process is less efficient, and senes-
cent cells trigger the decline in transparency. Al-
though pathogenesis is largely unclear, patients
with genetic predisposition to early-onset cat-
aract can help to define molecular mechanisms.

RATIONALE:Lack of the lipid kinase PI3K-C2a

(phosphatidylinositol-4-phosphate 3-kinase

catalytic subunit type 2a) causes premature cat-

aracts in fish, mice, and humans. This indicates

that PI3K-C2ais involved in the maintenance

of an evolutionarily conserved mechanism that

protects the lens from the loss of transparency.

On the basis of this, we aimed to define the role

of PI3K-C2ain the lens, starting from the no-

tion that this kinase is involved in mitosis and

that correct cell division protects from senes-

cence and eventually cataract development.

RESULTS:We found that PI3K-C2aplayed a spe-

cific role in the last step of cell division, called

cytokinetic abscission. At the end of the mitotic

process, the two nascent daughter cells form a

contractile ring that constricts the membrane

and produces an intercellular bridge that is

eventually cleaved through biochemical reac-

tions orchestrated by a specific organelle, the

midbody. PI3K-C2awas found to be enriched at

the midbody, where it produces a specific lipid

moiety known as phosphoinositide (3,4) bis-

phosphate [PI(3,4)P 2 ]. PI(3,4)P 2 appeared to

be required for efficient organization of the

membrane-severing machinery, a multiprotein

aggregate in which a cascade of three serially

acting, ESCRT proteins–containing complexes

eventually cleave the intercellular bridge. At

the midbody, the endosomal sorting complexes

required for transport I (ESCRT I) complex trig-

gers the enucleation of the ESCRT II protein

aggregate and then that of the membrane-

severing ESCRT III machinery. A key compo-

nent of the ESCRT II complex, named VPS36,

anchored on locally preformed PI(3,4)P 2 to prop-

erly stabilize the ESCRT II protein aggregate at

the midbody. This was found in fish, mice, and

humans, indicating that this process has been

conserved throughout vertebrate evolution. With-

out PI3K-C2aand its lipid product PI(3,4)P 2 ,

the ESCRT machinery loses efficiency, and cyto-

kinesis is delayed. Prolonged cytokinesis triggers

the expression of p16INK4A and the activation of

the transcriptional program, leading to senes-

cence, likely protecting against the genomic

instability that ensues cell division after refu-

sion and tetraploidization. However, cytokinesis

evolved as a resilient cellular process, and re-

dundant pathways are common in the orga-

nization of the various ESCRT complexes. For

example, an alternative pathway to ESCRT III

organization that bypasses the need for an

ESCRT II aggregate relies on the function of

the linker protein ALIX. In the lens, ALIX was

poorly expressed, and the PI3K-C2a, PI(3,4)P 2 ,

and VPS36 pathway was specifically required

to protect lens cells from cytokinetic delay, se-

nescence, and ultimately, cataract formation.

CONCLUSION:This study provides evidence that

a pathway based on PI3K-C2a, PI(3,4)P 2 , and

VPS36 positioning at the midbody improves

robustness of cytokinetic abscission and is non-

redundant in the eye lens. Failure of this process

defines a pathogenetic mechanism of cataract

development, ultimately delineating a path link-

ing ESCRT dysfunction to senescence.▪

RESEARCH

SCIENCEscience.org 10 DECEMBER 2021•VOL 374 ISSUE 6573 1339

The list of author affiliations is available in the full article online.

*Corresponding author. Email: [email protected] (F.G.);

[email protected] (E.H.)

Cite this article as F. Gulluniet al.,Science 374 , eabk0410

(2021). DOI: 10.1126/science.abk0410

READ THE FULL ARTICLE AT

https://doi.org/10.1126/science.abk0410

Abscission Prolonged cytokinesis

Cytokinesis

↑ β-gal

↑ p16INK4A

↑ p21

↑ SASP

Normal lens Cataract

Wild type PI3K-C2α/PI(3,4)P2/

ESCRT-II-loss

Human

Mouse Zebrafish

PI(3,4)P2

ESCRT-II

midbodyid

Senescence

During cytokinesis, PI3K-C2aproduced PI(3,4)P 2 (red) at the midbody, triggering the recruitment of the
ESCRT-II subunit VPS36 (light blue).When PI3K-C2a, PI(3,4)P 2 , or VPS36 is lost, the secondary ingression,
where abscission occurs, does not form properly, resulting in prolonged cytokinesis. This leads to aneuploidy
and early onset of senescence, which is particularly evident in the lens epithelium, resulting in cataract.