ESCRT-III controls nuclear envelope deformation induced by progerin

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, caused by mutation in the gene encoding lamin A/C, which produces a truncated protein called progerin. In cells from HGPS patients, progerin accumulates at the nuclear membrane (NM), where it causes NM deformations. In this study, we investigated whether progerin-induced NM deformation involved ESCRT-III, a protein complex that remodels nuclear and cytoplasmic membranes. The ESCRT-III protein CHMP4B was recruited to sites of aberrant NM proliferation in human cells ectopically expressing progerin and in patient-derived HGPS fibroblasts. Derepression of NM deformation in these cells was observed following depletion of CHMP4B or an ESCRT-III adaptor, ALIX. Treatment with rapamycin (which induce autophagic clearance of progerin and reverse progerin-induced cellular phenotypes) down-regulated progerin-induced NM deformation, whereas treatment with bafilomycin A1 (an inhibitor of autophagy and lysosome-based degradation) or CHMP4B depletion antagonized the effects of rapamycin. These results indicate that the ALIX-mediated ESCRT-III pathway plays a suppressive role in progerin-induced NM deformation and suggest that autophagy down-regulates progerin-induced NM deformation in a manner dependent on ESCRT-III machinery.

When in Need of an ESCRT: The Nature of Virus Assembly Sites Suggests Mechanistic Parallels between Nuclear Virus Egress and Retroviral Budding

“…Viruses 2021, 13, x FOR PEER REVIEW 8 of 14 The parallels between retroviral budding and viral nuclear egress described here point toward a remarkable replication mechanism reached by divergent virus families. These viruses operate via a particle assembly pathway that is topologically equivalent to cellular mechanisms [74][75][76]. Using the assembly components of either of these viruses as tools to study the role of the ESCRTs in these processes could help address longstanding questions in the field of membrane biology as to why some damaged membranes are reparable and sealable, while others are recycled, both via an ESCRT-dependent mechanism [76,77].…”

“…These viruses operate via a particle assembly pathway that is topologically equivalent to cellular mechanisms [74][75][76]. Using the assembly components of either of these viruses as tools to study the role of the ESCRTs in these processes could help address longstanding questions in the field of membrane biology as to why some damaged membranes are reparable and sealable, while others are recycled, both via an ESCRT-dependent mechanism [76,77]. Simultaneously, these studies may also uncover previously overlooked mechanisms of how viruses selectively recruit the ESCRT machinery at very discrete steps to avoid being recycled themselves [12].…”

“…One example of a scenario in which the nuclear envelope is recycled rather than repaired is in the membrane damage induced by defects in Lamin A in cases of Progeria [76]. Progeria is a disease caused by the accumulation of a truncated form of Lamin A that severely compromises nuclear architecture [80].…”

“…In the analysis of patient samples with clinical manifestations of the disease, it was shown that ALIX was the principal recruitment factor for the autophagy machinery used for the degradation of membrane-damaged areas, rather than for the repair of these areas. This study did not investigate the molecular basis behind ALIX recruitment to these sites, but proposed a mechanism by which excess membrane protein is sensed and marked for degradation via ALIX as part of nuclear envelope quality control surveillance [76]. Lamins readily adopt intermediate filaments as part of the nuclear cytoskeleton [81].…”

Host and Viral Factors Involved in Nuclear Egress of Herpes Simplex Virus 1

“…In fibroblasts from HGPS patients, truncated LMNA (also referred to as ‘progerin’) accumulates in the nucleus and engenders NM deformations that affect nuclear blebbing and perinuclear vesicle formation [ 45 ]. The ALIX-mediated ESCRT-III pathway plays a suppressive role in progerin-induced NM deformation, perhaps through vesicle-mediated cytoplasmic transport [ 144 ] ( Figure 4 B,E). If so, herpesviruses may highjack this system to facilitate nuclear egress of capsids.…”