Abstract
MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes to the nucleus, where it can interact with chromatin and regulate gene expression, through deubiquitination of histone H2A and non-catalytic contacts with other transcriptional regulators. A cytosolic form of MYSM1 protein was also recently described and demonstrated to regulate signal transduction pathways of innate immunity, by promoting the deubiquitination of TRAF3, TRAF6, and RIP2. In this work we review the current knowledge on the molecular mechanisms of action of MYSM1 protein in transcriptional regulation, signal transduction, and potentially other cellular processes. The functions of MYSM1 in different cell types and aspects of mammalian physiology are also reviewed, highlighting the key checkpoints in hematopoiesis, immunity, and beyond regulated by MYSM1. Importantly, mutations in MYSM1 in human were recently linked to a rare hereditary disorder characterized by leukopenia, anemia, and other hematopoietic and developmental abnormalities. Our growing knowledge of MYSM1 functions and mechanisms of actions sheds important insights into its role in mammalian physiology and the etiology of the MYSM1-deficiency disorder in human.
Highlights
Assuming that the reversion mutation originated in a single hematopoietic stem cell (HSC), we can conclude that restoration of MYSM1 function provided a very strong selective advantage and allowed one HSC clone to reconstitute normal wild-type hematopoiesis in competition with a large pool of MYSM1-deficient stem and progenitor cells
Recent studies indicated an alternative function for MYSM1 as a regulator of the signal transduction pathways of innate immunity in the cytosol, independent of MYSM1-mediated regulation of gene expression at chromatin [3,8]
Loss of cytosolic MYSM1 function was implicated in the enhanced production of inflammatory cytokine and type-I interferons seen in Mysm1-/- macrophages
Summary
Myb-like, SWIRM, and MPN domains 1 (MYSM1) has emerged as an essential regulator of hematopoiesis, immunity, and other aspects of mammalian physiology. It is primarily a nuclear chromatin-interacting protein, with orthologues found only in the vertebrate species, indicating more recent evolutionary origins and suggesting specialized biological functions. MYSM1 comprises SANT, SWIRM, and MPN domains (Figure 1). The SWIRM domain of MYSM1, in contrast, does not have direct DNA binding activity [4], and it is a common domain-type. Our knowledge of the physiological substrates of MYSM1 DUB-catalytic activity continues to expaOndu.rHknisotownleedHg2eAo,fmthoenopuhbyisqiuoiltoigniactaeldsautbKst1r1a9te, swoafsMthYeSfiMrs1t sDuUbsBt-rcaatetaolyf tMicYaScMtiv1ittyo cboendtiensucreisbetod e(Hxp2aAnKd1. Hgeonwe MexYpSreMss1iocnooppreorfialteessowf idthifftehreenotthmeramDUmBaslitaonrceeglul ltaytpeetshreegmeanionms pe-owoirdlye ulannddesrcsatopoedo.f FhuisrttohneermHo2rAe, uMbYiqSuMiti1naactitoivnitaiensdatghaeingsetnpeoelyxuprbeiqssuioitninpatreodfilfeosrmofsdoifffherisetnotnme aHm2mAaaltiaDnNceAlldtyampeasgreefmoaciin[s15p,1o6o]rloyr uangadienrssttoootdh.eFrulertshsewrmelol-rceh, aMraYcStMeri1zaecdtiuvbitiiqesuaitginaaintestdphoilsytuobnieqsuaitnindahteisdtofonremvsaorfiahniststo[n1e1,H172,A18a]ttDo NouAr dkanmowagleedgfoechi a[v1e5,n16o]t boerenaginaivnessttiogtahteedr .less well-characterized ubiquitinated histones and histone variants [11,17,18] to our knowledge have not been investigated
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