LRSAM1 E3 ubiquitin ligase promotes proteasomal clearance of E6-AP protein

Mishra, Ribhav; Joshi, Vibhuti; Upadhyay, Arun; Amanullah, Ayeman; Dubey, Ankur Rakesh; Singh, Sarika; Dubey, Vikash Kumar; Poluri, Krishna Mohan; Jana, Nihar Ranjan; Mishra, Amit Kumar

doi:10.1016/j.cellsig.2020.109836

Cited by 3 publications

(1 citation statement)

References 63 publications

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“…Cytosolic chaperones, including HSP70, HSP40, HSP90, and HSP60, are primarily upregulated in cancer cells (Calderwood & Murshid, 2017). In the event where chaperones cannot fold the mutant proteins as in cancer cells, chaperones further interact with different quality control E3 ubiquitin ligases (LRSAM1, MGRN1, E6AP, and CHIP) and help in mediating the ubiquitination of these misfolded mutant substrates (Chhangani et al, 2012; A. Mishra, 2016; R. Mishra et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Autophagy based cellular physiological strategies target oncogenic progression

Kumar

Jagtap

Patwa

et al. 2021

Journal Cellular Physiology

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Evidence accumulated from past findings indicates that defective proteostasis may contribute to risk factors for cancer generation. Irregular assembly of abnormal proteins catalyzes the disturbance of cellular proteostasis and induces the ability of abnormal cellular proliferation. The autophagy mechanism plays a key role in the regular clearance of abnormal/poor lipids, proteins, and various cellular organelles. The results of functional and effective autophagy deliver normal cellular homeostasis, which establishes supportive metabolism and avoids unexpected tumorigenesis events. Still, the precise molecular mechanism of autophagy in tumor suppression has not been clear. How autophagy triggers selective or nonselective bulk degradation to dissipate tumor promotion under stress conditions is not clear. Under proteotoxic insults to knockdown the drive of tumorigenesis, it is critical for us to figure out the detailed molecular functions of autophagy in human cancers. The current article summarizes autophagy‐based theragnostic strategies targeting various phases of tumorigenesis and suggests the preventive roles of autophagy against tumor progression. A better understanding of various molecular partners of autophagic flux will improve and innovate therapeutic approaches based on autophagic‐susceptible effects against cellular oncogenic transformation.

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Section: Introductionmentioning

confidence: 99%

Autophagy based cellular physiological strategies target oncogenic progression

Kumar

Jagtap

Patwa

et al. 2021

Journal Cellular Physiology

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Double gene mutations of LRSAM1 and REEP1 and a new REEP1 mutation site found in a patient with amyotrophic lateral sclerosis with subjective paresthesia: A case report

Qin

Zhou

et al. 2023

Ibrain

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. Although dyskinesia is the most prominent clinical manifestation of ALS, with an in‐depth understanding of disease pathogenesis and clinical detection, more and more ALS patients are found to have nonmotor symptoms, such as sensory impairment. Genetic testing technology has developed rapidly in recent years. New genes have been proven to be involved in the pathogenesis of ALS. However, according to the existing research evidence, no literature has reported that patients with ALS have leucine‐rich repeats and sterility α mutations in motif 1 (LRSAM1) and receptor expression accessory protein 1 (REEP1). The mutation sites of REEP1 gene have not been reported, and the simultaneous mutations of two genes have not been reported. In the largest human gene mutation frequency database gnomad, the mutation sites of two genes are currently defined as new heterozygous variants with unclear clinical significance. Therefore, this article reports the clinical data of this case to further deepen the clinicians' understanding of the disease, and may provide evidence for further study of the new genotype–phenotype of LRSAM1 and REEP1.

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Siah2- and LRSAM1-mediated K63-linked ubiquitination of snakehead vesiculovirus nucleoprotein facilitates viral replication

Jiang,

Zhao,

Qin

et al. 2024

J Virol

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Nucleoprotein (N) is well known for its function in the encapsidation of the genomic RNAs of negative-strand RNA viruses, which leads to the formation of ribonucleoproteins that serve as templates for viral transcription and replication. However, the function of the N protein in other aspects during viral infection is far from clear. In this study, the N protein of snakehead vesiculovirus (SHVV), a kind of fish rhabdovirus, was proved to be ubiquitinated mainly via K63-linked ubiquitination. We identified nine host E3 ubiquitin ligases that interacted with SHVV N, among which seven E3 ubiquitin ligases facilitated ubiquitination of the N protein. Further investigation revealed that only two E3 ubiquitin ligases, Siah E3 ubiquitin protein ligase 2 (Siah2) and leucine-rich repeat and sterile alpha motif containing 1 (LRSAM1), mediated K63-linked ubiquitination of the N protein. SHVV infection upregulated the expression of Siah2 and LRSAM1, which maintained the stability of SHVV N. Besides, overexpression of Siah2 or LRSAM1 promoted SHVV replication, while knockdown of Siah2 or LRSAM1 inhibited SHVV replication. Deletion of the ligase domain of Siah2 or LRSAM1 did not affect their interactions with SHVV N but reduced the K63-linked ubiquitination of SHVV N and SHVV replication. In summary, Siah2 and LRSAM1 mediate K63-linked ubiquitination of SHVV N to facilitate SHVV replication, which provides novel insights into the role of the N proteins of negative-strand RNA viruses. IMPORTANCE Ubiquitination of viral protein plays an important role in viral replication. However, the ubiquitination of the nucleoprotein (N) of negative-strand RNA viruses has rarely been investigated. This study aimed at investigating the ubiquitination of the N protein of a fish rhabdovirus SHVV (snakehead vesiculovirus), identifying the related host E3 ubiquitin ligases, and determining the role of SHVV N ubiquitination and host E3 ubiquitin ligases in viral replication. We found that SHVV N was ubiquitinated mainly via K63-linked ubiquitination, which was mediated by host E3 ubiquitin ligases Siah2 (Siah E3 ubiquitin protein ligase 2) and LRSAM1 (leucine-rich repeat and sterile alpha motif containing 1). The data suggested that Siah2 and LRSAM1 were hijacked by SHVV to ubiquitinate the N protein for viral replication, which exhibited novel anti-SHVV targets for drug design.

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LRSAM1 E3 ubiquitin ligase promotes proteasomal clearance of E6-AP protein

Cited by 3 publications

References 63 publications

Autophagy based cellular physiological strategies target oncogenic progression

Autophagy based cellular physiological strategies target oncogenic progression

Double gene mutations of LRSAM1 and REEP1 and a new REEP1 mutation site found in a patient with amyotrophic lateral sclerosis with subjective paresthesia: A case report

Siah2- and LRSAM1-mediated K63-linked ubiquitination of snakehead vesiculovirus nucleoprotein facilitates viral replication

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