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Colchicine blocks tubulin heterodimer recycling by tubulin cofactors TBCA, TBCB and TBCE
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Orientador(es)
Resumo(s)
Colchicine has been used to treat gout and, more recently, to effectively prevent
autoinflammatory diseases and both primary and recurrent episodes of pericarditis. The
anti-inflammatory action of colchicine seems to result from irreversible inhibition of
tubulin polymerization and microtubule (MT) assembly by binding to the tubulin
heterodimer, avoiding the signal transduction required to the activation of the entire
NLRP3 inflammasome. Emerging results show that the MT network is a potential
regulator of cardiac mechanics. Here, we investigated how colchicine impacts in tubulin
folding cofactors TBCA, TBCB, and TBCE activities. We show that TBCA is abundant
in mouse heart insoluble protein extracts. Also, a decrease of the TBCA/β-tubulin
complex followed by an increase of free TBCA is observed in human cells treated with
colchicine. The presence of free TBCA is not observed in cells treated with other antimitotic agents such as nocodazole or cold shock, neither after translation inhibition
by cycloheximide. In vitro assays show that colchicine inhibits tubulin heterodimer
dissociation by TBCE/TBCB, probably by interfering with interactions of TBCE with
tubulin dimers, leading to free TBCA. Manipulation of TBCA levels, either by RNAi or
overexpression results in decreased levels of tubulin heterodimers. Together, these data
strongly suggest that TBCA is mainly receiving β-tubulin from the dissociation of preexisting heterodimers instead of newly synthesized tubulins. The TBCE/TBCB+TBCA
system is crucial for controlling the critical concentration of free tubulin heterodimers
and MT dynamics in the cells by recycling the tubulin heterodimers. It is conceivable
that colchicine affects tubulin heterodimer recycling through the TBCE/TBCB+TBCA
system producing the known benefits in the treatment of pericardium inflammation.
Descrição
Research Areas: Cell Biology ; Developmental Biology
Palavras-chave
Colchicine Tubulin cofactors TBCA TBCB TBCE Tubulin heterodimer dissociation Microtubule cytoskeleton
Contexto Educativo
Citação
Nolasco S, Bellido J, Serna M, Carmona B, Soares H, Zabala JC. 2021. Colchicine blocks tubulin heterodimer recycling by tubulin cofactors TBCA, TBCB and TBCE. Frontiers in Cell and Developmental Biology, 9:656273. Doi: 10.3389/fcell.2021.656273
Editora
Frontiers Media