Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis

Abstract

All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here, we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression, leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.

Mechanisms orchestrating the enzymatic activity and cellular functions of deubiquitinases

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Figure 5 Post - translational modifications of DUBs . 45 , 142 , 143 , 148 , 159 , 160 , 166 , 168 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 AT3, ataxin3; BAP1, BRCA1-associated protein 1; CC, coiled-coil; CFTR, cystic fibrosis transmembrane conductance regulator; CK2, casein kinase 2, CTD, C-terminal domain; DTT, dithiothreitol; DUB, deubiquitinase; FOXK, forkhead box class K; Glu, glutamylation; GSK3, glycogen synthase kinase 3; HBM, HCF-1 binding motif; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MJD, Machado–Joseph deubiquitinases; NFκB, nuclear factor kappa B; NES, nuclear exporting signal; NLS, nuclear localization signal; P, phosphorylation; QQQ, poly-Q region; SUMO, SUMOylation; SIM, SUMO-interacting motif; Ub, ubiquitin; UBA, Ub-associated domain; UCH, Ub-C terminal hydrolase; UIM, Ub-interacting motif; USP, ubiquitin carboxyl-terminal hydrolase; ZF, zing finger.

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Modification of Proteins by Metabolites in Immunity

“…Glutamylation has been shown to occur on the deubiquitinase BAP1 and modulates hematopoietic stem cell (HSC) selfrenewal and hematopoiesis (Xiong et al, 2020). Glutamylation of BAP1 promotes its ubiquitination and subsequent degradation, thereby hindering Hoxa1 expression, which is required for HSC self-renewal.…”

Regulators of tubulin polyglutamylation control nuclear shape and cilium disassembly by balancing microtubule and actin assembly

“…There have been several reports showing that TTLLs modify substrates other than MT. [70][71][72][73] For example, it has been shown that histone chaperones and the transcription factor KLF4 are substrates of TTLL1 and TTLL4, and TTLL5 glutamylates the retinitis pigmentosa GTPase regulator (RPGR). [71][72][73] It is possible that TPGC subunits could also modulate TTLL1 activity toward other, yet-to-be-defined substrates and contribute to the regulation of cilium assembly, nuclear morphology, and other unexplored processes.…”