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These enzymes are multiprotein complexes comprising SKP1, CUL1, RBX1, and an F-box protein that acts as a specificity factor by interacting with SKP1 through its F-box domain and recruiting substrates via other domains. E3 ligases are important players in the ubiquitination process, recognizing and transferring ubiquitin to substrates destined for degradation by proteasomes or processing by deubiquitinating enzymes. The ubiquitin-proteasome system (UPS) is the main regulator of intracellular proteolysis in eukaryotes and is required for parasites to alternate hosts in their life cycles, resulting in successful parasitism. <jats:italic>Leishmania<\/jats:italic> UPS is poorly investigated, and CRL1 in <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic>, the causative agent of visceral leishmaniasis in Latin America, is yet to be described. Here, we show that the <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> genes LINF_110018100 (SKP1-like protein), LINF_240029100 (cullin-like protein-like protein), and LINF_210005300 (ring-box protein 1 \u2013putative) form a LinfCRL1 complex structurally similar to the <jats:italic>H<\/jats:italic>. <jats:italic>sapiens<\/jats:italic> CRL1. Mass spectrometry analysis of the LinfSkp1 and LinfCul1 interactomes revealed proteins involved in several intracellular processes, including six F-box proteins known as F-box-like proteins (Flp) (data are available via ProteomeXchange with identifier PXD051961). The interaction of LinfFlp 1\u20136 with LinfSkp1 was confirmed, and using <jats:italic>in vitro<\/jats:italic> ubiquitination assays, we demonstrated the function of the LinfCRL1(Flp1) complex to transfer ubiquitin. We also found that <jats:italic>LinfSKP1<\/jats:italic> and <jats:italic>LinfRBX1<\/jats:italic> knockouts resulted in nonviable <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> lineages, whereas <jats:italic>LinfCUL1<\/jats:italic> was involved in parasite growth and rosette formation. Finally, our results suggest that LinfCul1 regulates the S phase progression and possibly the transition between the late S to G2 phase in <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic>. Thus, a new class of E3 ubiquitin ligases has been described in <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> with functions related to various parasitic processes that may serve as prospective targets for leishmaniasis treatment.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012336","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T17:36:05Z","timestamp":1721237765000},"page":"e1012336","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional characterization of Cullin-1-RING ubiquitin ligase (CRL1) complex in Leishmania infantum"],"prefix":"10.1371","volume":"20","author":[{"given":"Camila","family":"Rolemberg Santana Travaglini Berti de Correia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovana","family":"Maffei Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley","family":"Klaysson Pereira Regatieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayore Tamie","family":"Takamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Aparecida Rogerio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iran","family":"Malavazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Dam\u00e1rio Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeziel","family":"Dener Damasceno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitor","family":"Luiz da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Antonio Fernandes de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Santos da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Silva Nascimento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriano","family":"Cappellazzo Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Regina Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-2686","authenticated-orcid":true,"given":"Felipe Roberti","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"ppat.1012336.ref001","unstructured":"Leishmaniasis. 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