Characterization of the Testis-specific Proteasome Subunit α4s in Mammals

Uechi, Hiroyuki; Hamazaki, Jun; Murata, Shigeo

doi:10.1074/jbc.m114.558866

Cited by 52 publications

(64 citation statements)

References 31 publications

(32 reference statements)

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“…These include spermatoproteasomes, which contain an alternative α4 subunit, α4s, which is synthesized exclusively in male germ cells after their differentiation into spermatocytes[59,60], and testis-specific proteasomes, containing an alternative α6 subunit (α6T), which is essential for fertility in Drosophila[61,62]. Selective assembly of α subunit-substituted alternative CPs must distinguish alternative α subunits from their constitutive counterparts.…”

Section: The 20s Core Particle (Cp)mentioning

confidence: 99%

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

301

280

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The eukaryotic 26S proteasome is a large multi-subunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle (RP) and the 20S core particle (CP). Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the RP is to recognize, unfold, deubiquitylate and translocate substrates into the CP, which contains the proteolytic sites of the proteasome. Given the abundance and subunit complexity of the proteasome, the assembly of this ~2.5 MDa complex must be carefully orchestrated to ensure its correct formation. In recent years, significant advances have been made in the understanding of proteasome assembly, structure and function. Technical advances in cryo-electron microscopy have resulted in a series of atomic cryo-EM structures of both human and yeast 26S proteasomes. These structures have illuminated new intricacies and dynamics of the proteasome. In this review, we focus on the mechanisms of proteasome assembly, particularly in light of recent structural information.

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Section: The 20s Core Particle (Cp)mentioning

confidence: 99%

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

301

280

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“…While specialized proteasomes formed by alterations in ß-ring assembly are now well documented in mammalian cells, there is no evidence of somatic mammalian cells with alternative α rings. Mouse male germ cells have been shown to utilize another version of α4, called α4s; these paralogous subunits are 85% identical (94% similar) in sequence, and the functional differences, if any, between α4s proteasomes and canonical ones remain unknown (Uechi et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

2016

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Summary Targeted intracellular protein degradation in eukaryotes is largely mediated by the proteasome. Here we report formation of an alternative proteasome isoform in human cells, previously found only in budding yeast, which bears an altered subunit arrangement in the outer ring of the proteasome core particle. These proteasomes result from incorporation of an additional α4 (PSMA7) subunit in the position normally occupied by α3 (PSMA4). Assembly of ‘α4-α4’ proteasomes depends on the relative cellular levels of α4 and α3, and on the proteasome assembly chaperone PAC3. The oncogenic tyrosine kinases ABL and ARG and the tumor suppressor BRCA1 regulate cellular α4 levels and formation of α4-α4 proteasomes. Cells primed to assemble α4-α4 proteasomes exhibit enhanced resistance to toxic metal ions. Taken together, our results establish the existence of a novel mammalian proteasome isoform and suggest a potential role in enabling cells to adapt to environmental stresses.

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“…All isoforms of SPAG17 were completely abolished in the Pcdo mutant testis and so it seems that all C1a projection interactome were unable to form and this led to complete failure of sperm flagellum formation. Several testis specific proteasome/ubiquitin enzymes have been reported in rodents (Mochida, Tres et al 2000) (Nishito, Hasegawa et al 2006) and human (Mitchell, Woods et al 1991, Uechi, Hamazaki et al 2014. It is also possible that the mutant SPAG17 protein is degraded in the testis by a sperm specific proteasome-mediated quality control mechanism (Morales, Kong et al 2003, Zimmerman and Sutovsky 2009, Sutovsky 2011.…”

Section: Ependymal Cilia Show Normal Ultrastructure and Minimal Beatimentioning

confidence: 99%

A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

Abdelhamed

Lukacs

Cindrić

et al. 2020

Preprint

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Primary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects, and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed all the phenotypes of PCD. Whole exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele to be a nonsense mutation (c.5236A>T) in the Spag17 coding sequence creating a premature stop codon at position 1746 (K1746*). The Pcdo variant abolished different isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different motile cilia cell types. SPAG17 is required for proper development of the sperm flagellum, and is essential for either development or stability of the C1 microtubule structure within cilia, but not the brain ependymal cilia. We identified changes in ependymal cilia beating frequency but these did not apparently alter lateral ventricle cerebrospinal fluid (CSF) flow. Aqueductal (Aq) stenosis resulted in significantly slower and abnormally directed CSF flow and we suggest this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood, but have a significantly shortened life span with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 gene that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a novel and useful model for elucidating the molecular mechanisms underlying development of PCD in the mouse.

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Characterization of the Testis-specific Proteasome Subunit α4s in Mammals

Cited by 52 publications

References 31 publications

Proteasome Structure and Assembly

Proteasome Structure and Assembly

Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

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