Life science
Drug development, Medical & healthcare

The COMMD3/8 complex:
a novel therapeutic target for autoimmune diseases
Laboratory of Immune Response Dynamics, Immunology Frontier Research Center
Professor Kazuhiro Suzuki
https://researchmap.jp/kazuhirosuzuki?lang=en

The immune system depends on cell migration among various
anatomical sites, which is orchestrated by chemoattracting molecules and their receptors. We previously identified a protein complex consisting of copper metabolism MURR1 domain-containing(COMMD) 3 and COMMD8 (COMMD3/8 complex) as a signaling
adaptor for chemoattractant receptors that controls B cell migrationand promotes humoral immune responses. In our recent study,
the COMMD3/8 complex was shown to play an important role in
the pathogenesis of autoimmunity. Moreover, celastrol, an anti-inflammatory compound with a poorly defined mechanism of action,
was found to exert the immunosuppressive activity by inhibiting
the COMMD3/8 complex. Our study suggests that the COMMD3/8complex is a potentially druggable target in autoimmune diseases,
and points to celastrol as a lead pharmacologic candidate in thiscapacity.

be a useful strategy for the treatment of autoimmune diseases andsupport the consideration of celastrol as a lead candidate in thatendeavor.

Celastrol

Y149▍ Significance of the research and Future perspective
Having established the involvement of the COMMD3/8 complex
in a mouse model of rheumatoid arthritis, we demonstrated thatcelastrol exerts disease-ameliorating effects by targeting the COMMD3/8 complex. These findings provide a proof of concept that
disrupting the interaction between COMMD3 and COMMD8 may

C170
W130

L178

V151

L172

F168

L168

M160 I125▍ Background & Results

COMMD8Fig.1 A model of the celastrol bound COMMD3/8 complex.

P < 0.05

5Control
KO4Arthritis severity

Based on the essential role of the COMMD3/8 complex in humoral immune responses, we tested whether deficiency of theCOMMD3/8 complex alleviates collagen-induced arthritis, a B
cell-dependent mouse model of rheumatoid arthritis. COMMD3/8complex deficiency inhibited the progression of arthritis, which wasaccompanied by reduced production of autoantibodies. Thesefindings suggested that the COMMD3/8 complex contributes to thepathogenesis of rheumatoid arthritis.
Prompted by this finding, we performed a chemical screen toidentify inhibitors of the COMMD3/8 complex that could be used
for the treatment of autoimmune diseases. Since the function of
the COMMD3/8 complex depends on the association between
COMMD3 and COMMD8, we sought for compounds that disrupt
the physical interaction between the two COMMD proteins. Afterscreening of chemical libraries, we identified celastrol as the mostpotent compound. Celastrol is thought to be a major bioactive constituent of a medicinal herb, Tripterygium wilfordii, but its mechanism of action had been poorly understood.
Using site-directed mutagenesis, molecular dynamics simulations and liquid chromatography-tandem mass spectrometry, we
revealed that celastrol dissociates the COMMD3/8 complex bycovalently binding to C170 on COMMD3. Celastrol inhibited B cell
migration, suppressed humoral immune responses and blocked
progression of arthritis, recapitulating deficiency of the COMMD3/8complex. The immunosuppressive effects of celastrol were abolished in mice carrying a mutation substituting C170 on COMMD3to alanine, which rendered the COMMD3/8 complex resistant tocelastrol. These findings established that the COMMD3/8 complex
is the major target of celastrol.

COMMD3L175Control

32KO1 mm

10071421Days after disease onset

Fig.2 Effects of CMMD3/8 complex deficiency on arthritis.

P < 0.05

8Arthritis severity

Life science

AbstractControl
Celastrol

6Control4Celastrol

1 mm

20071421Days after disease onset
Fig.3 Effects of celastrol treatment on arthritis.

P a t e n t
Shirai, Taiichiro; Nakai, Akiko; Ando, Emiko et al. Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8complex. Sci. Immunol. 2023, 8 (81), eadc9324. doi: 10.1126/sciimmunol.adc9324
Nakai, Akiko; Fujimoto, Jun; Miyata, Haruhiko et al. The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors. J. Exp. Med.
2019, 216 (7), 1630-1647. doi: 10.1084/jem.20181494
UR
L https://ird.ifrec.osaka-u.ac.jp/en
K e y w o r d autoimmunity, rheumatoid arthritis, B cell, COMMD3/8 complex, celastrol
Tr e a t i s e