Microtubule organizing centers (MTOCs) come in various flavors, including spindle pole bodies in yeast, cilia or centrosomes in animal cells and non-centrosomal MTOCs in female oocytes and plant cells. In centrosome-containing cells, each centrosome comprises two centrioles that recruit and organize the pericentriolar material, where microtubule nucleation occurs1. During mitosis, the two centrosomes facilitate the assembly of a bipolar spindle, the machinery responsible for segregating chromosomes into two genetically identical daughter cells. The stability of centrosome numbers is ensured by the precise control of the centriole duplication cycle. Over the past 25 years, molecular characterization of the centriole duplication cycle has identified ubiquitin ligase activity and subsequent proteasome degradation of centriolar components as key events2. The control of centriole duplication helps prevent MTOC number defects and the formation of multipolar mitotic spindles, which can lead to abnormal cell division and aneuploidy. Recent analysis of mutations in the E3 ubiquitin ligase TRIM37 associated with Mulibrey (muscle, liver, brain, eye) nanism has revealed alternative mechanisms resulting in multipolarity3,4,5,6 (Fig. 1a).

Fig. 1: Requirements and function of TRIM37 in centrosomal/MTOC aggregate function.
figure 1

a, Left, TRIM37 loss of function (LOF) leads to ectopic cytoplasmic centrobin aggregates, which function as non-centriole MTOCs that lead to multipolar cell division. Middle, normal TRIM37 levels are permissive for bipolar spindle assembly and therefore normal cell division. Right, TRIM37 overexpression (OE) in cells that have lost their centrosomes. In these cells, the acentrosomal pathway relies on CEP192, a PCM component, to assemble a bipolar mitotic spindle. Increased TRIM37 levels lead to CEP192 degradation along with mitotic spindle collapse and mitotic catastrophe. The pink gradient represents TRIM37 levels. b, Schematic of a TRIM37 dimer, containing RING, B-box, coiled-coiled (CC) and TRAF domains, based on data from refs. 8,9. TRIM37 oligomerization and substrate recognition leads to activation of TRIM37, which can then attach ubiquitin (Ub) to substrates, leading to the degradation of substrate–TRIM37 complexes.

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In TRIM37-mutated cells or fibroblasts from individuals with Mulibrey nanism, ectopic cytoplasmic condensates that nucleate microtubules, acting as non-centrosomal MTOCs, assemble multipolar spindles, leading to abnormal cell division5,6. Mulibrey nanism is a rare autosomal recessive congenital disorder characterized by severe growth failure and tumor incidence7, likely due to defects in cell division caused by non-centrosomal MTOCs. The composition of non-centrosomal MTOCs in TRIM37-mutated cells varies across cell types but consistently includes centrobin, a daughter centriole component5,6. Interestingly, these ectopic cytoplasmic centrobin condensates do not contain centrioles and so do not represent bona fide centrosomes8,9. Instead, they function as non-centrosomal active microtubule nucleation centers, disrupting the expected bipolar spindle status.

The importance of TRIM37 extends beyond loss-of-function studies. In humans, TRIM37 is located on chromosome 17, and 17q23 amplicons leading to TRIM37 overexpression are found in individuals with breast cancer or neuroblastoma. Notably, TRIM37 overexpression is synthetically lethal in conjunction with PLK4 loss10,11. Inhibition of PLK4, the master centriole duplication kinase, causes cells to lose their centrioles, which in turn obliges the acentrosomal mitotic spindle assembly pathway to take over. The synthetic lethality observed is due to low levels of the pericentriolar material CEP192 protein, which are directly induced by TRIM37 overexpression. This is explained by the fact that acentriolar spindles require CEP192 localization at spindle poles and cells are therefore vulnerable to CEP192 loss, which results in mitotic catastrophe10,11. The common denominator in TRIM37 loss of function and TRIM37 overexpression is the resulting mitotic defects explained by the presence of ectopic cytoplasmic aggregates or lower levels of pericentriolar material. This fits with the idea that this ubiquitin ligase directly controls the abundance of key proteins to ensure mitotic fidelity. These findings prompt the question of how these components are protected from TRIM37 activity under normal physiological conditions.

TRIM37 belongs to the tripartite motif–containing (TRIM) family of proteins, comprising around 70 members involved in various cellular functions including proliferation control, apoptosis, stress response and even viral infection restriction12. TRIM proteins contain an E3 ligase RING domain, a B-box and a coiled-coil domain, defining them as a type of RBCC protein. Along with the RBCC domains at their N termini, TRIM proteins contain different C-terminal domains12.

Two recent studies published in Nature Structural & Molecular Biology, by Yeow et al.8 and by Bellaart et al.9, investigated the molecular mechanisms involved in TRIM37’s clearance of centrosomal assemblies. Based on complementation studies in which the endogenous TRIM37 protein is replaced by constructs expressing specific mutations, some present in Mulibrey nanism, the articles report that the E3 RING ligase domain destabilized cytoplasmic centrobin or centrosomal CEP192. These results demonstrate that the E3 ubiquitin ligase activity is responsible for dissolving these protein assemblies in the cytoplasm and at the centrosome. Alpha-fold models predicted a T-shaped antiparallel dimer with one RING and one B-box domain at each extremity, while the two TRAF domains are arranged below, on the T stalk (Fig. 1b). Both studies identified mutations that abolished dimerization and higher-order oligomerization. Because TRIM37 protein could be found in both lower- and higher-molecular-mass complexes, the authors tested the function of the RING–B box–coiled-coil domains in promoting higher-order structures, which appeared to depend on the B-box domain.

Unlike other TRIM family members, TRIM37 contains a TRAF domain resembling the SPRY domain present in TRIM5, which restricts retroviral propagation of the HIV-1 virus13. In that case, the SPRY domain is involved in viral recognition, triggering a downstream response culminating in proteasome-dependent viral capsid degradation. It was hypothesized that the TRAF domain might have a similar role in recognizing TRIM37 substrates. Supporting this hypothesis, Yeow et al.8 and Bellaart et al.9 observed that mutations in the TRAF domain prevented TRIM37 from binding its substrates, leading to abnormal accumulation of centrosomal assemblies.

Next, it was important to test what allows TRIM37 to distinguish centrobin/CEP192 protein populations that should be ubiquitinated from those that should be maintained. Using an elegant optogenetic approach, Yeow et al.8 tested the role of protein clustering in recruiting and activating TRIM37. Upon light exposure, the domain of centrobin involved in TRIM37 was forced to cluster in the cytoplasm, leading to TRIM37 recruitment and activation to clear these structures8. Interestingly, substrate-induced clustering triggered the degradation of the entire substrate–TRIM37 complex, providing information about the dynamics of TRIM37 regulation.

Overall, the two studies8,9 reveal the mechanisms involved in clearing cytoplasmic aggregates and pericentriolar components to avoid ectopic microtubule nucleation. TRIM37 dimerization and consequent oligomerization driven by RING–RING domain interactions and conformational changes triggered by B-box domains allow substrate recognition in a TRAF-domain-mediated manner. Substrate binding and subsequent ubiquitination are sensitive to the state of the substrate itself, and substrate clustering appears to be geometrically sensed by the B-box region, as further shown by Bellaart et al.9.

With these results in mind, and considering the localization of TRIM37 to the cytoplasm and centrosomes, it will be important to determine the extent of TRIM37 activity in specific cell types, as well as in cells that grow cilia or that are fully differentiated and therefore no longer assemble a mitotic spindle. Proximity ligation assays revealed a multitude of possible interactors and likely substrates of TRIM37 (ref. 8), identifying exciting directions for future research.