TRIM family: Pleiotropy and diversification through homomultimer and heteromultimer formation

Napolitano, L.M.; Meroni, Germana

doi:10.1002/iub.580

Cited by 150 publications

(127 citation statements)

References 66 publications

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“…32 Accumulating data indicate that the TRIM family represents one of the largest classes of single-protein, RING-containing, E3 ubiquitin-ligases. 33,34 We and others have demonstrated that Trim17 is a bona fide E3 ubiquitin-ligase. 25,35 In addition, we have shown that the E3 activity of Trim17 is both necessary and sufficient for the initiation of neuronal apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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Short-term proteasome inhibition has been shown to prevent neuronal apoptosis. However, the key pro-survival proteins that must be degraded for triggering neuronal death are mostly unknown. Here, we show that Mcl-1, an anti-apoptotic Bcl-2 family member, is degraded by the proteasome during neuronal apoptosis. Using primary cultures of cerebellar granule neurons deprived of serum and KCl, we found that ubiquitination and proteasomal degradation of Mcl-1 depended on its prior phosphorylation by GSK3, providing the first insight into post-translational regulation of Mcl-1 in neurons. In a previous study, we have reported that the E3 ubiquitin-ligase Trim17 is both necessary and sufficient for neuronal apoptosis. Here, we identified In the nervous system, apoptosis plays a critical role both during development and in neurodegenerative diseases. 1 In many neuronal types, apoptosis is triggered through the intrinsic pathway of caspase activation that involves the release of cytochrome c from mitochondria. The proteins of the Bcl-2 family, that comprises both anti-apoptotic (Bcl-2, Bcl-x L , Mcl-1y) and pro-apoptotic members (Bax, Bak, Bimy), play an essential role in the regulation of apoptosis by controlling the integrity of the outer mitochondrial membrane and the release of apoptogenic factors such as cytochrome c. 2 Amongst the anti-apoptotic proteins of the Bcl-2 family, Mcl-1 (Myeloid cell leukemia 1) is characterized by a short half-life. 3 Its rapid degradation by the proteasome has been shown to be required for initiation of the apoptotic cascade in several cell lines. [4][5][6][7] For a long time, little attention was paid to a potential role for Mcl-1 in the nervous system because initial studies did not detect it in neurons. However, Mcl-1 is expressed in cerebellar granule neurons (CGNs) in vivo, 8 and Mcl-1 expression has been associated with neuroprotection in the hippocampus. 9 More recently, elegant studies using different conditional Mcl-1 mouse mutants, showed that Mcl-1 is required for neuronal development, that loss of Mcl-1 sensitizes neurons to DNA damage-induced apoptosis and that Mcl-1 negatively regulates autophagy in starved neurons. 10,11 Therefore, Mcl-1 appears to play a crucial role in neuronal survival. Nevertheless, post-translational regulation of Mcl-1 has never been studied in neurons.In the present study, we report for the first time that Mcl-1 is degraded by the proteasome during neuronal apoptosis. We found that Mcl-1 degradation depended on its prior phosphorylation by glycogen synthase kinase 3 (GSK3), in primary cultures of CGNs deprived of serum and KCl. This phosphorylation of Mcl-1 favored its physical interaction with Trim17, a novel E3 ubiquitin-ligase involved in neuronal apoptosis. Moreover, our present data provide evidence that Trim17 contributes to the ubiquitination and the proteasomal degradation of Mcl-1 in neurons. As such, we define a novel molecular mechanism for regulation of Mcl-1 and initiation of apoptosis. ResultsMcl-1 is degraded by the proteasome during...

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Section: Discussionmentioning

confidence: 99%

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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“…Tripartite motif (TRIM) E3 ligases constitute one of the largest subfamilies of RING E3s and regulate many cellular processes with a large proportion of TRIM family members being important in the regulation of innate immune responses (Meroni & Diez‐Roux, 2005; Hatakeyama, 2011; Napolitano & Meroni, 2012; Rajsbaum et al , 2014). TRIM ligases share a conserved domain architecture that consists of an N‐terminally located TRIM motif and a C‐terminal region of variable composition that often contains protein interaction domains and may act as a substrate‐recognition module.…”

Section: Introductionmentioning

confidence: 99%

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

et al. 2016

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TRIM E3 ubiquitin ligases regulate a wide variety of cellular processes and are particularly important during innate immune signalling events. They are characterized by a conserved tripartite motif in their N‐terminal portion which comprises a canonical RING domain, one or two B‐box domains and a coiled‐coil region that mediates ligase dimerization. Self‐association via the coiled‐coil has been suggested to be crucial for catalytic activity of TRIMs; however, the precise molecular mechanism underlying this observation remains elusive. Here, we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity. The crystal structure of a complex between the TRIM25 RING domain and an ubiquitin‐loaded E2 identifies the structural and mechanistic features that promote a closed E2~Ub conformation to activate the thioester for ubiquitin transfer allowing us to propose a model for the regulation of activity in the full‐length protein. Our data reveal an unexpected diversity in the self‐association mechanism of TRIMs that might be crucial for their biological function.

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“…"Linker" segments of unknown structure typically separate both the RING and B-box domains (L1) and the coiledcoil and terminal effector domains (L2). The coiled-coil region mediates oligomerization, and both homooligomeric and heterooligomeric TRIMs have been described (7)(8)(9)(10)(11)(12)(13). Furthermore, many TRIM proteins form higher-order assemblies in vitro and form punctate or fibrous structures in cells (14)(15)(16).…”

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confidence: 99%

The tripartite motif coiled-coil is an elongated antiparallel hairpin dimer

Sanchez

Okreglicka

Chandrasekaran

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

167

231

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Tripartite motif (TRIM) proteins make up a large family of coiledcoil-containing RING E3 ligases that function in many cellular processes, particularly innate antiviral response pathways. Both dimerization and higher-order assembly are important elements of TRIM protein function, but the atomic details of TRIM tertiary and quaternary structure have not been fully understood. Here, we present crystallographic and biochemical analyses of the TRIM coiled-coil and show that TRIM proteins dimerize by forming interdigitating antiparallel helical hairpins that position the Nterminal catalytic RING domains at opposite ends of the dimer and the C-terminal substrate-binding domains at the center. The dimer core comprises an antiparallel coiled-coil with a distinctive, symmetric pattern of flanking heptad and central hendecad repeats that appear to be conserved across the entire TRIM family. Our studies reveal how the coiled-coil organizes TRIM25 to polyubiquitylate the RIG-I/viral RNA recognition complex and how dimers of the TRIM5α protein are arranged within hexagonal arrays that recognize the HIV-1 capsid lattice and restrict retroviral replication.antiparallel dimer | disulfide crosslinking | X-ray crystallography T ripartite motif (TRIM) proteins make up the largest superfamily of RING E3 ubiquitin ligases, with more than 100 members in the human proteome (1, 2). TRIM proteins function in a variety of cellular pathways, and many regulate innate immunity and/or mediate antiviral responses. Antiviral TRIMs include TRIM25, which regulates the IFN response to RNA viruses (3, 4), and TRIM5α, which senses and inhibits early stages of retroviral replication (5, 6).TRIM proteins share a common N-terminal domain organization, termed the tripartite or RBCC (RING, B-box, coiled-coil) motif, followed by variable C-terminal protein recognition domains ( Fig. 1 A and B). "Linker" segments of unknown structure typically separate both the RING and B-box domains (L1) and the coiledcoil and terminal effector domains (L2). The coiled-coil region mediates oligomerization, and both homooligomeric and heterooligomeric TRIMs have been described (7-13). Furthermore, many TRIM proteins form higher-order assemblies in vitro and form punctate or fibrous structures in cells (14-16). For example, TRIM5α assembly allows the protein to function as a cytosolic patternrecognition receptor that can intercept the incoming capsids of diverse retroviruses, including HIV-1 (6). This results in species-specific "restriction" of viral replication (5), capsid dissociation (5, 6), and induction of innate immune responses (17). Retroviral capsids are recognized through a remarkable mechanism of multivalent pattern recognition. TRIM5α forms a homodimer (10, 11, 18), which can further assemble into a 2D lattice of linked hexagons (18). The hexagonal TRIM5α net matches the symmetry and spacing of the retroviral capsid surface lattice, thereby positioning multiple C-terminal B30.2/SPRY domains to interact with their repeating binding epitopes on the capsid.Struct...

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TRIM family: Pleiotropy and diversification through homomultimer and heteromultimer formation

Cited by 150 publications

References 66 publications

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

The tripartite motif coiled-coil is an elongated antiparallel hairpin dimer

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