Nature - USA (2020-10-15)

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significantly decreased the levels of TH17 cells in mouse splenocytes
(Fig. 4f).
To provide additional support for these findings, we also used
Zdhhc7-knockout mice in the colitis model. On the basis of our
mechanistic model (Fig. 4i), we predicted that knockout of Zdhhc7
should also reduce DSS-induced colitis. Indeed, we found that Zdhhc7
knockout decreased TH17 cell differentiation and protected mice from
DSS-induced colitis (Fig. 4g, h, Extended Data Fig. 10f ). We therefore
suggest that the STAT3 palmitoylation–depalmitoylation cycle could
be a promising therapeutic target for TH17-related immune disorders.

Discussion
The transcription factor STAT3 is known to be recruited to the plasma
membrane and phosphorylated by JAK2 under specific stimulation.
p-STAT3 then migrates to the nucleus and promotes the expression
of target genes^3 ,^12. However, very little is known about the mechanism
by which STAT3 is recruited to the membrane. Here we showed that
Cys108 of STAT3 is palmitoylated by DHHC7 (and to a lesser extent by
DHHC3), which promotes membrane recruitment and phosphoryla-
tion by JAK2. Although palmitoylation is well-known to be important
for membrane distribution and signalling outputs^1 ,^2 , how palmitoyla-
tion and depalmitoyation are balanced to promote signalling has
been a fundamental unaddressed question. Palmitoylation anchors
STAT3 to the cell membranes, but for nuclear translocation it must
be depalmitoylated. We showed that APT2 contributes to the nuclear
translocation of p-STAT3 by selectively depalmitoylating p-STAT3 over
unphosphorylated STAT3. These results suggest a model in which the
palmitoylation–depalmitoylation cycle, rather than being a futile cycle,
drives STAT3 activation (Fig. 4i). Without this cycle, even though STAT3
can still form homodimers and translocate to the nucleus, most STAT3
is present in its inactive unphosphorylated state (Fig. 4i).
Constitutive activation of STAT3 contributes to TH17 cell differentiation
in patients with immune disorders, leading to poor clinical outcomes^7 ,^12.
STAT3 has been proven to be an effective target for inhibiting TH17 cell
differentiation and attenuating colitis in mouse models of IBD^7. Our work
demonstrates that the palmitoylation–depalmitoylation cycle of STAT3
affects TH17 cell differentiation, and suggests that both DHHC7 and APT2
could be new therapeutic targets for treating colitis. Because TH17 cells are
a key factor affecting the course and severity of various immune disorders
such as IBD, hyper-IgE syndrome and arthritis^12 ,^19 ,^20 , the palmitoylation–
depalmitoylation cycle of STAT3 could be a potential therapeutic target
for the treatment of many other autoimmune disorders.
Post-translational modifications are particularly suited for mediat-
ing cell signalling, as evidenced by the well-known signalling func-
tions of phosphorylation and ubiquitination. Protein S-palmitoylation
was discovered as a post-translational modification several decades
ago^21 , yet despite the fact that close to 3,000 proteins in humans are
known to undergo this modification, very little is understood about
how it contributes to cell signalling^1. This study demonstrates that a
palmitoylation–depalmitoylation cycle can proceed in a specific direc-
tion to promote cell signalling, with the direction of the cycle in this
case ensured by the specificity of APT2 towards the phosphorylated

substrate. This example could provide important insights for under-

standing the signalling functions of S-palmitoylation in numerous

other cell signalling processes.

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availability are available at https://doi.org/10.1038/s41586-020-2799-2.

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